Increase of catechol-O-methyltransferase activity in rat brain microglia after intrastriatal infusion of fluorocitrate, a glial toxin.
Reenilä I,Tuomainen P,Soinila S,Männistö P T
Neuroscience letters
Striatal catechol-O-methyltransferase (COMT), monoamine oxidase B (MAO-B; an astroglial enzyme), alkaline phosphodiesterase I (PDE; a microglia/macrophage marker) and tyrosine hydroxylase (TH; catecholaminergic neuron marker) activities were analyzed biochemically 1-3 days after infusion of fluorocitrate, an astrocyte damaging agent. Astrocytes, microglia and neurons were stained immunohistochemically with specific antibodies (against glial fibrillary acidic protein, OX-42 and TH, respectively) and with COMT antiserum. Three days after fluorocitrate infusion the activity of MAO-B was reduced, whereas COMT and PDE activities were increased. The elevation of COMT immunoreactivity co-localized to microglial cells, but not to astrocytes. In conclusion, this is the first report indicating that microglia contains COMT activity which may be increased in pathological conditions.
10.1016/s0304-3940(97)00502-8
Effects of Selegiline in a retroviral rat model for neurodegenerative disease.
Czub M,Czub S,Gosztonyi G,Koutsilieri E,Sopper S,Müller J G,Gerlach M,Riederer P,ter Meulen V
Journal of neurovirology
Upon inoculation into neonatal rats, murine leukemia virus (MuLV) NT40 causes a non-inflammatory degeneration of the central nervous system. While microglia cells appear to be the major target cells within the brain parenchyma for neurovirulent MuLV, degenerating neurons do not express retroviral gene products. In order to protect rats from neuronal damage we treated retrovirally infected rats once with monoamine oxidase (MAO) B inhibitor Selegiline which--under different conditions--exerts neuroprotective effects. Unexpectedly, when administered at 17 days post-infection (d.p.i.) a single intraperitoneal dose of Selegilin (1 mg/kg bodyweight) significantly shortened the incubation period for neurological disease. In contrast, Selegiline given in a lower dosage (0.05 mg/kg bodyweight) and/or at a different time point (13 d.p.i.) at the low (0.05 mg/kg bodyweight) and the high dose (1.0 mg/kg bodyweight) had no effect on the outcome of neurological disease. Animals treated with Selegiline (1.0 mg/kg bodyweight at 17 d.p.i.) contained higher amounts of viral loads in the CNS, higher numbers of brain cells expressing major histocompatibility complex class II molecules, and exhibited inhibition of MAO-B in comparison to untreated yet infected (control) animals. Supposedly, Selegiline activated the major target cell population of the CNS for MuLV-NT40, microglia, with the consequence of enhanced susceptibility for retroviral infection and triggered endogenous mechanism(s) involved in the pathogenesis of retroviral neurodegeneration.
10.3109/13550289909045374
The MAO Inhibitor Tranylcypromine Alters LPS- and Aβ-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD.
Park HyunHee,Han Kyung-Min,Jeon Hyongjun,Lee Ji-Soo,Lee Hyunju,Jeon Seong Gak,Park Jin-Hee,Kim Yu Gyung,Lin Yuxi,Lee Young-Ho,Jeong Yun Ha,Hoe Hyang-Sook
Cells
Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo.
10.3390/cells9091982
Ladostigil prevents gliosis, oxidative-nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats.
Shoham Shai,Bejar Corina,Kovalev Eugenia,Schorer-Apelbaum Donna,Weinstock Marta
Neuropharmacology
Glial activation and oxidative-nitrative stress occur at an early stage in Alzheimer's disease (AD). In a rat model of AD, deficits in cerebral glucose utilization and memory were seen 3-4 weeks after intracerebroventricular (icv) injection of streptozotocin (STZ). This study examined whether icv STZ induced glial activation and oxidative-nitrative stress preceded the memory deficits and whether they could be prevented by ladostigil a novel drug, a cholinesterase and monoamine oxidase inhibitor with neuroprotective activity. One week after STZ injection activated microglia and astrocytes were seen in the cortex, around the cannula penetration area, in the hippocampal CA1 region, corpus callosum, medial and lateral septum. The activated astrocytes showed a significant increase in nitrotyrosine immunoreactivity, a measure of oxidative-nitrative stress. Only 3 weeks later were deficits in episodic (object recognition test) and spatial memory (place recognition) seen in STZ-injected rats. Daily oral administrations of ladostigil (1mg/kg) for 1 week, before and after STZ prevented the glial changes, increase in nitrotyrosine immunoreactivity and memory deficits. Taken together the data support the role of glial activation and oxidative-nitrative stress in discrete brain areas in the aetiology of memory deficits and indicate a potential mechanism for their prevention by drug treatment.
10.1016/j.neuropharm.2006.10.005
HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that selectively reverse HIV latency.
Llewellyn George N,Alvarez-Carbonell David,Chateau Morgan,Karn Jonathan,Cannon Paula M
Journal of neurovirology
Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in microglia, perivascular macrophages, and astrocytes. Studying HIV in the brain has been challenging, since live cells are difficult to recover from autopsy samples and primate models of SIV infection utilize viruses that are more myeloid-tropic than HIV due to the expression of Vpx. Development of a realistic small animal model would greatly advance studies of this important reservoir and permit definitive studies of HIV latency. When radiation or busulfan-conditioned, immune-deficient NSG mice are transplanted with human hematopoietic stem cells, human cells from the bone marrow enter the brain and differentiate to express microglia-specific markers. After infection with replication competent HIV, virus was detected in these bone marrow-derived human microglia. Studies of HIV latency in this model would be greatly enhanced by the development of compounds that can selectively reverse HIV latency in microglial cells. Our studies have identified members of the CoREST repression complex as key regulators of HIV latency in microglia in both rat and human microglial cell lines. The monoamine oxidase (MAO) and potential CoREST inhibitor, phenelzine, which is brain penetrant, was able to stimulate HIV production in human microglial cell lines and human glial cells recovered from the brains of HIV-infected humanized mice. The humanized mice we have developed therefore show great promise as a model system for the development of strategies aimed at defining and reducing the CNS reservoir.
10.1007/s13365-017-0604-2
Oxidative stress indices in Parkinson's disease : biochemical determination.
Youdim M B,Drigues N,Mandel S
Methods in molecular medicine
ABSTRUCT: Parkinson's disease (PD) is associated with progressive degeneration of melanin-containing dopamine neuron cell bodies arising in the substantia nigra pars compacta (SNpc) and projecting terminals to the striatum. The disease is best characterized biochemically as a deficiency of striatal dopamine. The mechanism of neurodegeneration remains an enigma despite a large body of investigation and several hypotheses (1-5). In the past decade much has been learned about the chemical pathology of the disease. This progress has been helped by elucidation of the mechanism of the neurotoxic actions of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which are used to induce animal models of this disease. Thus, the most valid current hypothesis concerning the pathogenesis of idiopathic PD is progressive oxidative stress (OS), which can generate excessive reactive oxygen species (ROS) selectively in the SNpc (1-9), and subsequent biochemical abnormalities (Table 1). In addition, the ROS scavenging system may also diminish, which would exaggerate the condition leading to accumulation of ROS. In PD, it is thought that both these events occur; Table 1 gives a summary of the biochemical changes identified to date in the SNpc of PD patients. Iron, monoamine oxidase B (MAO-B), copper/zinc superoxide dismutase (Cu/Zn-SOD), and heme oxygenase (radical producing) are increased; reduced glutathione (GSH) and vitamin C (radical scavenging) are decreased. Whether OS is a primary or secondary event in PD has not been established, but when it does occur, OS can lead to a cascade of events resulting in the demise of the nigrostriatal dopaminergic neurons. One approach toward protection of such neurons is the use of radical scavengers or iron chelators as neuroprotective drugs (10). Table 1 Biochemical Alterations in Substantia Nigra of Parkinson's Disease Indicating Oxidative Stress Elevated Decreased Iron (in microglia, astrocytes, oligodendrocytes, and melanized dopamine neurons and mitochondria) GSH (GSSG unchanged); GSH/GSSG ratio decreased Mitochondrial complex I Ferritin Calcium binding protein (calbindin 28) Mitochondrial monoamine oxidase B Transferrin and transferrin receptor Lipofuscin Vitamins E and C Ubiquitin Copper Cu/Zn-superoxide dismutase Cytotoxic cytokines (TNF-a, IL-1, IL-6) Inflammatory transcription factor NFKB Heme oxygenase-1 Ratio of oxidized to reduced glutathione (GSSG/GSH) Nitric oxide Neuromelanin.
10.1385/1-59259-142-6:137
DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline.
Trudler Dorit,Weinreb Orly,Mandel Silvia A,Youdim Moussa B H,Frenkel Dan
Journal of neurochemistry
DJ-1 is an oxidative stress sensor that localizes to the mitochondria when the cell is exposed to oxidative stress. DJ-1 mutations that result in gene deficiency are linked to increased risk of Parkinson's disease (PD). Activation of microglial stress conditions that are linked to PD may result in neuronal death. We postulated that DJ-1 deficiency may increase microglial neurotoxicity. We found that down-regulation of DJ-1 in microglia using an shRNA approach increased cell sensitivity to dopamine as measured by secreted pro-inflammatory cytokines such as IL-1β and IL-6. Furthermore, we discovered that DJ-1-deficient microglia had increased monoamine oxidase activity that resulted in elevation of intracellular reactive oxygen species and nitric oxide leading to increased dopaminergic neurotoxicity. Rasagaline, a monoamine oxidase inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and significantly reduced neurotoxicity. Moreover, we discovered that DJ-1-deficient microglia have reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), previously suggested as a risk factor for pro-inflammation in neurodegenerative diseases. Further studies of DJ-1-mediated cellular pathways in microglia may contribute useful insights into the development of PD providing future avenues for therapeutic intervention
10.1111/jnc.12633
Ladostigil prevents age-related glial activation and spatial memory deficits in rats.
Weinstock Marta,Luques Lisandro,Poltyrev Tatyana,Bejar Corina,Shoham Shai
Neurobiology of aging
Oxidative stress and glial activation occur in the aging brain. Ladostigil is a new monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitor designed for the treatment of Alzheimer's disease. It has neuroprotective and antioxidant activities in cellular models at much lower concentrations than those inhibiting MAO or AChE. When ladostigil (1mg/kg/day) was given for 6 months to 16-month-old rats it prevented the age-related increase in activated astrocytes and microglia in several hippocampal and white matter regions and increased proNGF immunoreactivity in the hippocampus towards the levels in young rats. Ladostigil also prevented the age-related reduction in cortical AChE activity and the increase in butyrylcholinesterase activity in the hippocampus, in association with the reduction in gliosis. The immunological and enzymatic changes in aged rats were associated with improved spatial memory. Ladostigil treatment had no effect on memory, glial or proNGF immunoreactivity in young rats. Early treatment with ladostigil could slow disease progression in conditions like Alzheimer's disease in which oxidative stress and inflammatory processes are present.
10.1016/j.neurobiolaging.2009.06.004
Chronic harmine treatment has a delayed effect on mobility in control and socially defeated rats.
Psychopharmacology
INTRODUCTION:Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation are involved in the development and progression of the disease. The monoamine oxidase A inhibitor drug harmine was suggested to have both antidepressant and anti-inflammatory properties and may, therefore, be a potential candidate for treatment of depression. AIM:The goal of this study was to assess the effects of harmine on behavior, brain BDNF levels, and microglia activation in control rats and a rat model of social stress. MATERIAL AND METHODS:Rats were submitted to 5 consecutive days of repeated social defeat (RSD) or control conditions. Animals were treated daily with harmine (15 mg/kg) or vehicle from day 3 until the end of the experiment. To assess the effects of harmine treatment on behavior, the sucrose preference test (SPT) was performed on days 1, 6, and 15, the open field test (OFT) on days 6 and 14, and the novel object recognition test (NOR) on day 16. Brain microgliosis was assessed using [C]PBR-28 PET on day 17. Animals were terminated on day 17, and BDNF protein concentrations in the hippocampus and frontal cortex were analyzed using ELISA. RESULTS:RSD significantly decreased bodyweight and increased anxiety and anhedonia-related parameters in the OFT and SPT on day 6, but these behavioral effects were not observed anymore on day 14/15. Harmine treatment caused a significant reduction in bodyweight gain in both groups, induced anhedonia in the SPT on day 6, and significantly reduced the mobility and exploratory behavior of the animals in the OFT mainly on day 14. PET imaging and the NOR test did not show any significant effects on microglia activation and memory, respectively. BDNF protein concentrations in the hippocampus and frontal cortex were not significantly affected by either RSD or harmine treatment. DISCUSSION:Harmine was not able to reverse the acute effects of RSD on anxiety and anhedonia and even aggravated the effect of RSD on bodyweight loss. Moreover, harmine treatment caused unexpected side effects on general locomotion, both in RSD and control animals, but did not influence glial activation status and BDNF concentrations in the brain. In this model, RSD-induced stress was not strong enough to induce long-term effects on the behavior, neuroinflammation, or BDNF protein concentration. Thus, the efficacy of harmine treatment on these delayed parameters needs to be further evaluated in more severe models of chronic stress.
10.1007/s00213-020-05483-2
Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult.
Dhami K S,Churchward M A,Baker G B,Todd K G
Molecular and cellular neurosciences
Depression is one of the most common disorders appearing following a stroke, and is also a major factor limiting recovery and rehabilitation in stroke patients. Antidepressants are the most common prescribed treatment for depression and have shown to have anti-inflammatory properties within the central nervous system (CNS). The major source of pro-inflammatory factors within the CNS is from activated microglia, the innate immune cells of the CNS. Antidepressants have been shown to promote midbrain and hippocampal neuronal survival following an ischemic insult and this survival is mediated through the anti-inflammatory effects on microglia, but the effects on cortical neuronal survival after this insult have yet to be investigated. The present study aimed to test and compare antidepressants from three distinct classes (tricyclics, monoamine oxidase inhibitors, and selective serotonin-reuptake inhibitors [SSRIs]) on the release of inflammatory factors and amino acids from activated microglia and whether altering this release could affect cortical neuronal viability after an ischemic insult. Primary microglia were treated with 1 μg/ml LPS and/or 10 μM antidepressants, and the various factors released into medium were assayed. Co-cultures consisting of microglia and primary cortical neurons were used to assess the effects of antidepressant-treated activated microglia on the viability of ischemic injured neurons. Of the antidepressants tested, most decreased the release of the proinflammatory factors nitric oxide, tumor necrosis factor-alpha, and interleukin 1-beta from activated microglia. Fluoxetine and citalopram, the SSRIs, decreased the release of the amino acids glutamate and d-serine from LPS-activated microglia. oxygen-glucose deprived (OGD) cortical neurons cocultured with LPS-activated microglia pre-treated with fluoxetine and citalopram showed greater survival compared to injured neurons co-cultured with untreated activated microglia. Microglial release of glutamate and d-serine was shown to be the most important factor mediating neuronal survival following antagonism studies. To our knowledge, our results demonstrate for the first time that fluoxetine and citalopram decrease the release of glutamate and d-serine from LPS-activated microglia and this causes an increase in the survival of OGD-injured cortical neurons after co-culture.
10.1016/j.mcn.2013.07.006
Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis.
Morsali Damineh,Bechtold David,Lee Woojin,Chauhdry Summen,Palchaudhuri Upayan,Hassoon Paula,Snell Daniel M,Malpass Katy,Piers Thomas,Pocock Jennifer,Roach Arthur,Smith Kenneth J
Brain : a journal of neurology
Axonal degeneration is a major cause of permanent disability in the inflammatory demyelinating disease multiple sclerosis, but no therapies are known to be effective in axonal protection. Sodium channel blocking agents can provide effective protection of axons in the white matter in experimental models of multiple sclerosis, but the mechanism of action (directly on axons or indirectly via immune modulation) remains uncertain. Here we have examined the efficacy of two sodium channel blocking agents to protect white matter axons in two forms of experimental autoimmune encephalomyelitis, a common model of multiple sclerosis. Safinamide is currently in phase III development for use in Parkinson's disease based on its inhibition of monoamine oxidase B, but the drug is also a potent state-dependent inhibitor of sodium channels. Safinamide provided significant protection against neurological deficit and axonal degeneration in experimental autoimmune encephalomyelitis, even when administration was delayed until after the onset of neurological deficit. Protection of axons was associated with a significant reduction in the activation of microglia/macrophages within the central nervous system. To clarify which property of safinamide was likely to be involved in the suppression of the innate immune cells, the action of safinamide on microglia/macrophages was compared with that of the classical sodium channel blocking agent, flecainide, which has no recognized monoamine oxidase B activity, and which has previously been shown to protect the white matter in experimental autoimmune encephalomyelitis. Flecainide was also potent in suppressing microglial activation in experimental autoimmune encephalomyelitis. To distinguish whether the suppression of microglia was an indirect consequence of the reduction in axonal damage, or possibly instrumental in the axonal protection, the action of safinamide was examined in separate experiments in vitro. In cultured primary rat microglial cells activated by lipopolysaccharide, safinamide potently suppressed microglial superoxide production and enhanced the production of the anti-oxidant glutathione. The findings show that safinamide is effective in protecting axons from degeneration in experimental autoimmune encephalomyelitis, and that this effect is likely to involve a direct effect on microglia that can result in a less activated phenotype. Together, this work highlights the potential of safinamide as an effective neuroprotective agent in multiple sclerosis, and implicates microglia in the protective mechanism.
10.1093/brain/awt041
Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers.
Bascuñana Pablo,Gendron Thibault,Sander Kerstin,Jahreis Ina,Polyak Andras,Ross Tobias L,Bankstahl Marion,Arstad Erik,Bankstahl Jens P
Epilepsia
OBJECTIVE:Identification of patients at risk of developing epilepsy before the first spontaneous seizure may promote the development of preventive treatment providing opportunity to stop or slow down the disease. METHODS:As development of novel radiotracers and on-site setup of existing radiotracers is highly time-consuming and expensive, we used dual-centre in vitro autoradiography as an approach to characterize the potential of innovative radiotracers in the context of epilepsy development. Using brain slices from the same group of rats, we aimed to characterise the evolution of neuroinflammation and expression of inhibitory and excitatory neuroreceptors during epileptogenesis using translational positron emission tomography (PET) tracers; F-flumazenil ( F-FMZ; GABA receptor), F-FPEB (metabotropic glutamate receptor 5; mGluR5), F-flutriciclamide (translocator protein; TSPO, microglia activation) and F-deprenyl (monoamine oxidase B, astroglia activation). Autoradiography images from selected time points after pilocarpine-induced status epilepticus (SE; baseline, 24 and 48 hours, 5, 10 and 15 days and 6 and 12-14 weeks after SE) were normalized to a calibration curve, co-registered to an MRI-based 2D region-of-interest atlas, and activity concentration (Bq/mm ) was calculated. RESULTS:In epileptogenesis-associated brain regions, F-FMZ and F-FPEB showed an early decrease after SE. F-FMZ decrease was maintained in the latent phase and further reduced in the chronic epileptic animals, while F-FPEB signal recovered from day 10, reaching baseline levels in chronic epilepsy. F-flutriciclamide showed an increase of activated microglia at 24 hours after SE, peaking at 5-15 days and decreasing during the chronic phase. On the other hand, F-deprenyl autoradiography showed late astrogliosis, peaking in the chronic phase. SIGNIFICANCE:Autoradiography revealed different evolution of the selected targets during epileptogenesis. Our results suggest an advantage of combined imaging of inter-related targets like glutamate and GABA receptors, or microglia and astrocyte activation, in order to identify important interactions, especially when using PET imaging for the evaluation of novel treatments.
10.1111/epi.16353
Banisteriopsis caapi extract: Implications for neuroinflammatory pathways in Locus coeruleus lesion rodent model.
Journal of ethnopharmacology
ETHNOPHARMACOLOGY RELEVANCE:Ayahuasca is a beverage obtained from the decoctions of Banisteriopsis caapi (Spruce ex Griseb.) Morton and Psychotria viridis Ruiz & Pav., used throughout the Amazon as a medicinal beverage for healing and spiritual exploration. The Banisteriopsis caapi extract consists of harmine, harmaline, and tetrahydroharmine (THH); which inhibit the isoforms of monoamine oxidase A and B. In the central nervous system (CNS), it can increase the norepinephrine (NE) concentration, produced in the Locus coeruleus (LC), reducing inflammation that is associated with some neurological disease, such as Parkinson's disease and Alzheimer's disease. AIM OF THE STUDY:evaluate the effects of treatment with B. caapi extract on the neuroinflammatory profile in animals with selective LC lesions. MATERIAL AND METHODS:male Wistar rats with LC lesions induced by 6-hydroxydopamine were treated with B. caapi extract. Subsequently, behavioral tests were conducted, including the elevated plus maze, rotarod, and open field. Tyrosine hydroxylase positive (TH+) neurons and IBA-1 positive microglia were quantified from the LC inflammatory markers and free radical products were assessed. RESULTS:Both 6-Hydroxydopamine hydrochloride and the Banisteriopsis caapi extract causes reduction of LC neurons, at the concentration and frequency used. The LC depletion and the treatment of B. caapi extract interfere with locomotion. B. caapi extract and the LC lesion increased the number and activation of inflammatory cells, such as microglia. B. caapi extract decreases IL-10 in the hippocampus and BDNF gene expression. CONCLUSION:This study suggests that B. caapi extract (at the concentration and frequency used) promotes noradrenergic neuron depletion and creates a proinflammatory environment in the CNS.
10.1016/j.jep.2024.118775
Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice.
Takahashi Kohei,Nakagawasai Osamu,Nemoto Wataru,Kadota Shogo,Isono Jinichi,Odaira Takayo,Sakuma Wakana,Arai Yuichiro,Tadano Takeshi,Tan-No Koichi
Neuropharmacology
Our previous study suggested that the non-competitive N-methyl-d-aspartate receptor antagonist memantine (MEM) inhibits dopamine (DA) reuptake and turnover by inhibiting brain monoamine oxidase. Clinical studies have reported that MEM may improve depressive symptoms; however, specific mechanisms underlying this effect are unclear. We performed emotional behavior, tail suspension, and forced swimming tests to examine whether MEM has antidepressant effects in olfactory bulbectomized (OBX) mice, an animal model of depression. Subsequently, we investigated the effects of MEM on the distribution of tyrosine hydroxylase (TH), altered microglia morphometry, and astrocyte and cell proliferation in the hippocampus with immunohistochemistry. We also investigated MEM effects on the levels of norepinephrine (NE), DA, and their metabolites with high performance liquid chromatography, and of neurotrophic, proinflammatory, and apoptotic molecules in the hippocampus with western blotting. Forty-two days after surgery, OBX mice showed depressive-like behaviors, as well as decreased levels of monoamines, reduced cell proliferation, and lower levels of TH, phospho(p)-TH (ser31 and ser40), p-protein kinase A (PKA), p-DARPP-32, p-ERK1/2, p-CREB, brain-derived neurotrophic factor (BDNF), doublecortin, NeuN, and Bcl-2 levels. In contrast, the number of activated microglia and astrocytes and the levels of Iba1, GFAP, p-IκB-α, p-NF-κB p65, TNF-α, IL-6, Bax, and cleaved caspase-3 were increased in the hippocampus. These changes (except for those in NE and Bax) were reversed with chronic administration of MEM. These results suggest that MEM-induced antidepressant effects are associated with enhanced hippocampal cell proliferation and neuroprotection via the PKA-ERK-CREB-BDNF/Bcl-2-caspase-3 pathway and increased DA levels.
10.1016/j.neuropharm.2018.04.013
Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer's Disease.
Olsen Malin,Aguilar Ximena,Sehlin Dag,Fang Xiaotian T,Antoni Gunnar,Erlandsson Anna,Syvänen Stina
Molecular imaging and biology
PURPOSE:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-L-[C]deprenyl ([C]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during Aβ pathology progression. PROCEDURES:APP mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [C]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. Aβ and GFAP levels were also measured with ELISA in brain homogenates. RESULTS:The intrabrain levels of aggregated Aβ and reactive astrocytes were found to be elevated in APP compared with WT mice. GFAP and vimentin expression increased with age, i.e., with Aβ pathology, in the APP mice. This was not the case for in vivo marker [C]DED that showed elevated binding of the same magnitude in APP mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. CONCLUSIONS:MAO-B levels are increased early in Aβ pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant Aβ plaque formation. Thus, [C]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of AD progression but does not measure the total extent of astrogliosis at advanced stages of Aβ pathology.
10.1007/s11307-017-1153-z
Synthesis and evaluation of isoprenylation-resveratrol dimer derivatives against Alzheimer's disease.
European journal of medicinal chemistry
A series of resveratrol dimer derivatives against Alzheimer's disease (AD) was obtained by structural modification and transformation using resveratrol as substrate. Biological analysis revealed that these derivatives had moderate inhibitory activity against human monoamine oxidase B (hMAO-B). In particular, 3 and 7 showed the better inhibitory activity for hMAO-B (IC = 3.91 ± 0.23 μM, 0.90 ± 0.01 μM) respectively. Compound 3 (IC = 46.95 ± 0.21 μM for DPPH, 1.43 and 1.74 trolox equivalent by ABTS and FRAP method respectively), and 7 (IC = 35.33 ± 0.15 μM for DPPH, 1.70 and 1.97 trolox equivalent by ABTS method and FRAP method respectively) have excellent antioxidant effects. Cellular assay shown that 3 and 7 had lower toxicity and were resistant to neurotoxicity induced by oxidative toxins (HO, rotenone and oligomycin-A). More importantly, the selected compounds have neuroprotective effects against ROS generation, HO-induced apoptosis and a significant in vitro anti-inflammatory activity. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that 3 and 7 would be predominant to cross the blood-brain barrier. In this study, mouse microglia BV2 cells were used to establish cell oxidative stress injury model with HO and to explore the protective effect and mechanism of 3 and 7. In general, 3 and 7 can be considered candidates for potential treatment of AD.
10.1016/j.ejmech.2018.11.040
Neuroprogression and Immune Activation in Major Depressive Disorder.
Meyer Jeffrey H
Modern trends in pharmacopsychiatry
Traditionally, the neurobiology of major depressive disorder (MDD) has been largely considered from the perspective of the state of major depressive episodes (MDE) versus being in remission, but the current accumulation of disease markers, largely acquired cross-sectionally, is strongly suggestive of neuroprogressive aspects of MDD. This chapter focuses on the changes in disease markers involved in the reorganization of the nervous system in MDD, including the translocator protein (TSPO; an index of microglial activation), glial fibrillary acidic protein (GFAP; an index of astroglial activation), [11C]harmine (a marker of monoamine oxidase A; MAO-A), and several other indices (metabotropic glutamate receptor 5 [mGluR5], excitatory amino acid transporters, and magnetic resonance imaging spectroscopy measurements) of glutamate dysregulation. These are markers of processes involved in immune activation, oxidative stress, and chronic glucocorticoid exposure. Positron emission tomography studies of the TSPO distribution volume, a marker of microglial activation, provide strong evidence for microglial activation throughout the gray matter of the brain during MDE of MDD. In postmortem studies, GFAP reductions in the orbitofrontal cortex, anterior cingulate cortex, and hippocampus indicate a deficit in reactive astroglia. Elevated MAO-A levels are present throughout the gray matter of the brain, including affect-modulating brain regions, starting in high-risk states for MDE such as the early postpartum period, perimenopause, heavy cigarette smoking, heavy alcohol intake, and prior to MDE recurrence. Evidence is accumulating for glutamate dysregulation, with some findings of reduced glutamate transporter density in the orbitofrontal cortex, and decreased mGluR5 density. Collectively, these changes suggest an imbalance in the immune system with increased microglial activation and decreased astroglial activation, continued elevations of the MAO-A level, and, likely, the development of extracellular glutamate dysregulation. Many of these imbalances involve processes implicated in increased oxidative stress, apoptosis, and neurodegeneration. Future studies are required to assess potential therapeutics targeting these processes to ameliorate progression of MDD.
10.1159/000470804
The anti-parkinsonian drug zonisamide reduces neuroinflammation: Role of microglial Na 1.6.
Hossain Muhammad M,Weig Blair,Reuhl Kenneth,Gearing Marla,Wu Long-Jun,Richardson Jason R
Experimental neurology
Parkinson's disease (PD), the second most common age-related progressive neurodegenerative disorder, is characterized by dopamine depletion and the loss of dopaminergic (DA) neurons with accompanying neuroinflammation. Zonisamide is an-anti-convulsant drug that has recently been shown to improve clinical symptoms of PD through its inhibition of monoamine oxidase B (MAO-B). However, zonisamide has additional targets, including voltage-gated sodium channels (Na), which may contribute to its reported neuroprotective role in preclinical models of PD. Here, we report that Na1.6 is highly expressed in microglia of post-mortem PD brain and of mice treated with the parkinsonism-inducing neurotoxin MPTP. Administration of zonisamide (20 mg/kg, i.p. every 4 h × 3) following a single injection of MPTP (12.5 mg/kg, s.c.) reduced microglial Na 1.6 and microglial activation in the striatum, as indicated by Iba-1 staining and mRNA expression of F4/80. MPTP increased the levels of the pro-inflammatory cytokine TNF-α and gp91, and this was significantly reduced by zonisamide. Together, these findings suggest that zonisamide may reduce neuroinflammation through the down-regulation of microglial Na 1.6. Thus, in addition to its effects on parkinsonian symptoms through inhibition of MAO-B, zonisamide may have disease modifying potential through the inhibition of Na 1.6 and neuroinflammation.
10.1016/j.expneurol.2018.07.005
Selective MAO-A and B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson's disease.
Youdim M B,Lavie L
Life sciences
In the absence of identification of either an endogenously or an exogenously derived dopaminergic neurotoxin, the most valid hypothesis currently envisaged for etiopathology of Parkinson's disease (PD) is selective oxidative stress (OS) in substantia nigra (SN). Although OS is not proven, a significant body of evidence from studies on animal and Parkinsonian brain neurochemistry supports it. This hypothesis is based on excessive formation of reactive oxygen species (O2 and OH.) and demise of systems involved with scavenging or preventing the formation of such radicals from H2O2, generated as a consequence of dopamine oxidation (autoxidation and deamination). Since MAO (monoamine oxidase A and B are the major H2O2 generating enzymes in the SN much attention has been paid to their selective inhibitors as symptomatic and neuroprotective agents in PD. Attention should also be given to radical scavengers (e.g. iron chelators, lipid peroxidative inhibitors and Vitamin E derivatives) as therapeutic neuroprotective agents in PD. This is considered valid since a significant elevation of iron is known to occur selectively in SN zone compacta and within the remaining melanized dopamine neurons of Parkinsonian brains. Although all the mechanism of iron induced oxygen free radical formation is not fully known there is no doubt that it participates with H2O2 (Fenton chemistry) to generate cytotoxic hydroxyl radical (OH.) and induce tissue OS and neurodegeneration in 6-hydroxydopamine model of PD. The dramatic proliferation of reactive amoeboid macrophages and microglia seen in SN of PD brains together with OS is highly compatible with an inflammatory process, similar to what has been observed in Alzheimer's disease and multiple sclerosis brains. This has led us to examine the ability of reactive macrophages to produce oxygen free radicals in response to nitric oxide (NO) production. The latter radical has been implicated in the excitotoxicity of glutaminergic neurons innervating the striatum and SN. Indeed we have now observed that in reactive macrophages NO acts as a signal transducer of O2 production which can synergize with dopamine oxidation.
10.1016/0024-3205(94)00388-2
Chemical characterization of small-molecule inhibitors of monoamine oxidase B synthesized from the Acanthopanax senticosus root with affinity ultrafiltration mass spectrometry.
He Yang,Wang Yimin,Zhang Xin,Zheng Zhong,Liu Shu,Xing Junpeng,Liu Zhiqiang,Zhou Hui
Rapid communications in mass spectrometry : RCM
RATIONALE:Discovering and identifying new small-molecule inhibitors of monoamine oxidase B (MAO-B) could provide the potential to treat many neurodegenerative diseases. METHODS:We employed affinity ultrafiltration liquid chromatography/tandem mass spectrometry (AUF-LC/MS ) to identify and characterize small-molecule inhibitors of MAO-B from a 30% ethanolic extract of Acanthopanax senticosus root (ASR). In vitro tests were performed in stimulated BV2 microglia to evaluate the anti-inflammatory effects of the ASR preparation. An in vitro enzyme activity assay, measuring half-maximal inhibitory concentrations (IC ) against MAO-B, determined the inhibitory activity of the potential MAO-B ligands. RESULTS:ASR treatment significantly inhibited NO release (p <0.01) and attenuated tumor necrosis factor (TNF)-α expression in stimulated BV2 microglia. Nine compounds were isolated from the ASR preparation as potential MAO-B inhibitors, identified as quinic acid, chlorogenic acid, isofraxidin, dicaffeoylquinic acid, pinoresinol diglucoside, medioresinol 4'-O-β-D-glucopyranoside, eletutheroside E, syringaresinol O-β-D-glucoside, and trihydroxyoctadecenoic acid, based on their tandem mass spectra. CONCLUSIONS:Our study provides critical data on compounds from ASR extracts which are suitable for the development of new MAO-B inhibitors as potential therapeutics for neurodegenerative diseases.
10.1002/rcm.8694
MAO-A Inhibition by Metaxalone Reverts IL-1β-Induced Inflammatory Phenotype in Microglial Cells.
Pallio Giovanni,D'Ascola Angela,Cardia Luigi,Mannino Federica,Bitto Alessandra,Minutoli Letteria,Picciolo Giacomo,Squadrito Violetta,Irrera Natasha,Squadrito Francesco,Altavilla Domenica
International journal of molecular sciences
Experimental and clinical studies have suggested that several neurological disorders are associated with the occurrence of central nervous system neuroinflammation. Metaxalone is an FDA-approved muscle relaxant that has been reported to inhibit monoamine oxidase A (MAO-A). The aim of this study was to investigate whether metaxalone might exert antioxidant and anti-inflammatory effects in HMC3 microglial cells. An inflammatory phenotype was induced in HMC3 microglial cells through stimulation with interleukin-1β (IL-1β). Control cells and IL-1β-stimulated cells were subsequently treated with metaxalone (10, 20, and 40 µM) for six hours. IL-1β stimulated the release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), but reduced the anti-inflammatory cytokine interleukin-13 (IL-13). The upstream signal consisted of an increased priming of nuclear factor-kB (NF-kB), blunted peroxisome proliferator-activated receptor gamma (PPARγ), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. IL-1β also augmented MAO-A expression/activity and malondialdehyde levels and decreased Nrf2 mRNA expression and protein levels. Metaxalone decreased MAO-A activity and expression, reduced NF-kB, TNF-α, and IL-6, enhanced IL-13, and also increased PPARγ, PGC-1α, and Nrf2 expression. The present experimental study suggests that metaxalone has potential for the treatment of several neurological disorders associated with neuroinflammation.
10.3390/ijms22168425
Preclinical and Potential Applications of Common Western Herbal Supplements as Complementary Treatment in Parkinson's Disease.
Morgan Luke A,Grundmann Oliver
Journal of dietary supplements
Parkinson's disease (PD) is a neurological disorder with a complex pathological etiology, which is not fully understood. Progression of PD may be the result of a buildup of iron in the substantia nigra, microglia-mediated neuroinflammation, dysfunctional mitochondria, or abnormal protein handling. Dopamine is the main neurotransmitter affected, but as the disease progresses, a decrease in all the brain's biogenic amines occurs. Current medication used in the treatment of PD aims to prevent the breakdown of dopamine or increase dopaminergic neurotransmission in the central nervous system. The complementary use of green tea (Camellia sinensis), red wine (Vitis vinifera), arctic root (Rhodiola rosea), and dwarf periwinkle (Vinca minor) may have a greater therapeutic effect than current pharmaceutical drugs, such as monoamine oxidase inhibitors or dopamine agonists alone. The bioactive components of these plants have been shown to have neuroprotective, antioxidant, anti-proteinopathies, neural-vasodilation, anti-inflammatory, and iron chelating potential. They may treat the disease at the cellular level by decreasing microglia activation, attenuating damage from radical oxygen species, supporting correct protein folding, chelating iron, increasing the substantia nigra blood flow, and promoting dopaminergic cell growth. Although these alternative medicines appear to have potential, further human clinical trials need to be conducted to determine whether they could have a greater therapeutic effect than conventional medicines alone.
10.1080/19390211.2016.1263710
Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?
Polanski Witold,Reichmann Heinz,Gille Gabriele
Expert review of neurotherapeutics
β-carbolines are potential endogenous and exogenous neurotoxins that may contribute to the pathogenesis of Parkinson's disease (PD). 9-methyl-β-carboline exhibits multimodal effects that could be beneficial in the treatment of PD. It shows stimulatory effects to dopaminergic neurons by increasing the expression of tyrosine hydroxylase and its transcription factors in pre-existing dopa decarboxylase immunoreactive neurons. Furthermore, 9-methyl-β-carboline has emerged as a substance with the rare property of a protective and regenerative/restorative potential for dopaminergic neurons by inducing gene expression of several neurotrophic factors and decreasing apoptotic cell signals. It reduces protein levels of α-synuclein and inhibits monoamine oxidase A and B. Finally, 9-methyl-β-carboline acts on multiple targets in the inflammatory cascade by inhibiting the proliferation of microglia, by decreasing chemotactic cytokines and by creating an anti-inflammatory environment in the CNS. This article summarizes our current knowledge of 9-methyl-carboline and discusses its potential role as a new drug for the treatment of PD.
10.1586/ern.11.1
Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography.
Saura J,Luque J M,Cesura A M,Da Prada M,Chan-Palay V,Huber G,Löffler J,Richards J G
Neuroscience
The aetiology and pathogenesis of Alzheimer's disease are currently poorly understood, but symptomatic disease is associated with amyloid plaques, neurofibrillary tangles, neuronal loss and numerous alterations of neurotransmitter systems in the CNS. Monoamine oxidase type B is known to be increased in Alzheimer diseased brains. The distribution and abundance of catalytic sites for monoamine oxidases A and B in post mortem human brains of 11 Alzheimer disease cases and five age-matched controls were investigated by quantitative enzyme radioautography. Using tritiated monoamine oxidase inhibitors (Ro41-1049 and lazabemide)--as high affinity substrates selective for monoamine oxidases A and B, respectively--it was found that monoamine oxidase B activity increased up to three-fold exclusively in temporal, parietal and frontal cortices of Alzheimer disease cases compared with controls. This increase was restricted to discrete patches (approximately 185 microns in diameter) which occupied approximately 12% of the cortical areas examined. In other brain regions (hippocampal formation >> caudate-putamen > cerebellum), patches of [3H]lazabemide-enriched binding were less abundant. [3H]Ro41-1049 binding (i.e. monoamine oxidase A) was unchanged in all tissues of diseased versus control brains. The monoamine oxidase B-enriched patches in all cortical regions correlated, in their distribution and frequency, with glial fibrillary acidic protein-immunoreactive clusters of astrocytes. Diffuse and mature beta-amyloid-immunoreactive senile plaques as well as patches of high density binding of [3H]PK-11195--a high-affinity ligand for peripheral-type (mitochondrial) benzodiazepine binding sites in microglia/macrophages--were found throughout Alzheimer diseased cortices. The up-regulation of monoamine oxidase B in plaque-associated astrocytes in Alzheimer's disease--in analogy to its proposed role in neurodegenerative disorders such as Parkinson's disease--might, indirectly, be a potential source of cytotoxic free radicals. Lazabemide, a selective reversible monoamine oxidase B inhibitor, is currently under clinical evaluation for the treatment of Parkinson's and Alzheimer's diseases. We conclude that enzyme radioautography with [3H]lazabemide is a reliable high resolution assay for plaque-associated astroglioses in Alzheimer's disease. Its clinical diagnostic utility for positron emission tomography or single photon emission computer tomography studies is being investigated.
10.1016/0306-4522(94)90311-5
Synthesis and biological evaluation of O-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents.
Bioorganic & medicinal chemistry
Design, synthesis, and biological evaluation of two series of O-benzyl-hispidol derivatives and the analogous corresponding O-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O-benzyl derivatives series. The most potential compound 2e of O-benzyl derivatives elicited sub-micromolar MAO-B IC of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O-benzyl derivatives showed only 0.95 MAO-B IC and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.
10.1016/j.bmc.2024.117826
Fluoxetine and its metabolite norfluoxetine induce microglial apoptosis.
Dhami Kamaldeep S,Churchward Matthew A,Baker Glen B,Todd Kathryn G
Journal of neurochemistry
Inflammatory insult to the central nervous system (CNS) can lead to development of depression, and subsequently depression is the most frequent psychiatric comorbidity following ischemic stroke, often limiting recovery and rehabilitation in patients. The initiators of inflammatory pathways in the CNS are microglia activated in response to acute ischemic stress, and anti-depressants have been shown to have anti-inflammatory effects in the CNS, promoting neuronal survival following ischemic insult. We have previously shown that the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and citalopram promote neuronal survival after oxygen-glucose deprivation, an in vitro model of ischemia, by attenuating the release of glutamate and D-serine from activated microglia. Interestingly, we found that fluoxetine-treated microglial cultures contained fewer numbers of cells compared to other groups and hypothesized that fluoxetine and citalopram attenuated the release of glutamate and D-serine by promoting the apoptosis of microglia. The present study aimed to test and compare antidepressants from three distinct classes (tricyclics, monoamine oxidase inhibitors, and SSRIs) on microglial apoptosis. Primary microglia were treated with 1 μg/mL lipopolysaccharide and/or 10 μM antidepressants, and various apoptotic markers were assayed. Fluoxetine and its metabolite norfluoxetine decreased protein levels in cell lysates, decreased cell viability of microglia, and increased the expression of the apoptotic marker cleaved-caspase 3 in microglia. Live/dead nuclear staining also showed that fluoxetine- or norfluoxetine-treated cultures contained greater numbers of dying microglial cells compared to vehicle-treated cultures. Cultures treated with citalopram, phenelzine, or imipramine showed no evidence of inducing microglial apoptosis. Our results demonstrate that fluoxetine and norfluoxetine induce the apoptotic death of microglia, which may serve as a mechanism to attenuate the release of glutamate and D-serine from activated microglia. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
10.1111/jnc.14661
Positional scanning of natural product hispidol's ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases.
Journal of enzyme inhibition and medicinal chemistry
Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative and neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic pathways and neuroinflammatory were addressed. A library of analogues of the natural product hispidol was prepared and evaluated for inhibition of monoamine oxidases (MAOs) isoforms. Several molecules emerged as selective potential MAO B inhibitors. The most promising compounds were further evaluated for their impact on microglia viability, induced production of proinflammatory mediators and MAO-B inhibition mechanism. Amongst tested compounds, was a safe potent competitive reversible MAO-B inhibitor and inhibitor of microglial production of neuroinflammatory mediators; NO and PGE. study provided insights into molecular basis of the observed selective MAO B inhibition. This study presents compound as a promising lead compound for management of neurodegenerative disease.
10.1080/14756366.2022.2036737
Attenuation of Ischemic Stroke-Caused Brain Injury by a Monoamine Oxidase Inhibitor Involves Improved Proteostasis and Reduced Neuroinflammation.
Liu Yanying,Feng Shelley,Subedi Kalpana,Wang Hongmin
Molecular neurobiology
Mitochondrial dysfunction and oxidative stress play a key role in ischemia/reperfusion (I/R) induced brain injury. We previously showed that ubiquilin-1 (Ubqln1), a ubiquitin-like protein, improves proteostasis and protects brains against oxidative stress and I/R induced brain injury. We demonstrate here that nialamide (NM), a non-selective monoamine oxidase (MAO) inhibitor, upregulated Ublqn1 and protected neurons from oxygen-glucose deprivation- and I/R-caused cell death in in vitro and in vivo, respectively. Post-ischemic administration of the NM in a stroke mouse model even at 3 h following I/R still reduced neuronal injury and improved functional recovery and survival. Treating stroke animals with NM also increased the association of Ubqln1 with mitochondria and decreased the total oxidized and polyubiquitinated protein levels. Intriguingly, NM-enhanced proteostasis was also associated with reduced I/R-caused neuroinflammation, as reflected by attenuated activation of microglia and astrocytes as well as reduced TNF-α level. Thus, our results suggest that MAO inhibition-induced neuroprotection following I/R involves improved proteostasis and reduced neuroinflammation.
10.1007/s12035-019-01788-2
Phenelzine (monoamine oxidase inhibitor) increases production of nitric oxide and proinflammatory cytokines via the NF-κB pathway in lipopolysaccharide-activated microglia cells.
Chung Hwan-Suck,Kim Hyunseong,Bae Hyunsu
Neurochemical research
Phenelzine is a potent monoamine oxidase inhibitor that is used in patients with depression. It is also well known that nitric oxide (NO) synthase inhibitors show preclinical antidepressant-like properties, which suggests that NO is involved in the pathogenesis of depression. The purpose of this study was to determine if phenelzine affects the production of NO and tumor necrosis factor-alpha (TNF-α) in activated microglia cells. BV-2 microglia cells and primary microglia cells were cultured in DMEM and DMEM/F12 and then cells were treated with LPS or LPS plus phenelzine for 24 h. The culture medium was collected for determination of NO, TNF-α, and IL-6 and cells were harvested by lysis buffer for Western blot analysis. Phenelzine increased the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS), as well as the release of TNF-α and IL-6 in BV-2 microglia cells. It is also confirmed that phenelzine increased the levels of NO, TNF-α and IL-6 in LPS-activated primary microglia cells. Phenelzine increased nuclear translocation of NF-κB by phosphorylation of IκB-α in LPS-activated microglia cells. These findings suggest that high doses of phenelzine could aggravate inflammatory responses in microglia cells that are mediated by NO and TNF-α.
10.1007/s11064-012-0833-y
Revisiting the Role of Astrocytic MAOB in Parkinson's Disease.
International journal of molecular sciences
Monoamine oxidase-B (MAOB) has been believed to mediate the degradation of monoamine neurotransmitters such as dopamine. However, this traditional belief has been challenged by demonstrating that it is not MAOB but MAOA which mediates dopamine degradation. Instead, MAOB mediates the aberrant synthesis of GABA and hydrogen peroxide (HO) in reactive astrocytes of Parkinson's disease (PD). Astrocytic GABA tonically suppresses the dopaminergic neuronal activity, whereas HO aggravates astrocytic reactivity and dopaminergic neuronal death. Recently discovered reversible MAOB inhibitors reduce reactive astrogliosis and restore dopaminergic neuronal activity to alleviate PD symptoms in rodents. In this perspective, we redefine the role of MAOB for the aberrant suppression and deterioration of dopaminergic neurons through excessive GABA and HO synthesis of reactive astrocytes in PD.
10.3390/ijms23084453
Monoamine Oxidase Inhibitors: A Review of Their Anti-Inflammatory Therapeutic Potential and Mechanisms of Action.
Ostadkarampour Mahyar,Putnins Edward E
Frontiers in pharmacology
Chronic inflammatory diseases are debilitating, affect patients' quality of life, and are a significant financial burden on health care. Inflammation is regulated by pro-inflammatory cytokines and chemokines that are expressed by immune and non-immune cells, and their expression is highly controlled, both spatially and temporally. Their dysregulation is a hallmark of chronic inflammatory and autoimmune diseases. Significant evidence supports that monoamine oxidase (MAO) inhibitor drugs have anti-inflammatory effects. MAO inhibitors are principally prescribed for the management of a variety of central nervous system (CNS)-associated diseases such as depression, Alzheimer's, and Parkinson's; however, they also have anti-inflammatory effects in the CNS and a variety of non-CNS tissues. To bolster support for their development as anti-inflammatories, it is critical to elucidate their mechanism(s) of action. MAO inhibitors decrease the generation of end products such as hydrogen peroxide, aldehyde, and ammonium. They also inhibit biogenic amine degradation, and this increases cellular and pericellular catecholamines in a variety of immune and some non-immune cells. This decrease in end product metabolites and increase in catecholamines can play a significant role in the anti-inflammatory effects of MAO inhibitors. This review examines MAO inhibitor effects on inflammation in a variety of and CNS and non-CNS disease models, as well as their anti-inflammatory mechanism(s) of action.
10.3389/fphar.2021.676239
A monoamine oxidase B inhibitor ethyl ferulate suppresses microglia-mediated neuroinflammation and alleviates ischemic brain injury.
Frontiers in pharmacology
Microglia are the resident macrophages in the brain, which play a critical role in post-stroke neuroinflammation. Accordingly, targeting neuroinflammation could be a promising strategy to improve ischemic stroke outcomes. Ethyl ferulate (EF) has been confirmed to possess anti-inflammatory properties in several disease models, including acute lung injury, retinal damage and diabetes-associated renal injury. However, the effects of EF on microglial activation and the resolution of post-stroke neuroinflammation remains unknown. Here, we found that EF suppressed pro-inflammatory response triggered by lipopolysaccharide (LPS) stimulation in primary microglia and BV2 cell lines, as well as post-stroke neuroinflammation in an transient middle cerebral artery occlusion (tMCAO) stroke model in C57BL/6 mice, consequently ameliorating ischemic brain injury. Furthermore, EF could directly bind and inhibit the activity of monoamine oxidase B (MAO-B) to reduce pro-inflammatory response. Taken together, our study identified a MAO-B inhibitor, Ethyl ferulate, as an active compound with promising potentials for suppressing post-stroke neuroinflammation.
10.3389/fphar.2022.1004215