Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.

Targeting of KOR by famotidine promotes OPC maturation differentiation and CNS remyelination via STAT3 signaling pathway.

This study aims to identify FDA-approved drugs that can target the kappa-opioid receptor (KOR) for the treatment of demyelinating diseases. Demyelinating diseases are characterized by myelin sheath destruction or formation that results in severe neurological dysfunction. Remission of this disease is largely dependent on the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLGs) in demyelinating lesions. KOR is an important regulatory protein and drug target for the treatment of demyelinating diseases. However, no drug targeting KOR has been developed due to the long clinical trials for drug discovery. Here, a structure-based virtual screening was applied to identify drugs targeting KOR among 1843 drugs of FDA-approved drug libraries, and famotidine was screen out by its high affinity cooperation with KOR as well as the clinical safety. We discovered that famotidine directly promoted OPC maturation and remyelination using the complementary in vitro and in vivo models. Administration of famotidine was not only effectively enhanced CNS myelinogenesis, but also promoted remyelination. Mechanically speaking, famotidine promoted myelinogenesis or remyelination through KOR/STAT3 signaling pathway. In general, our study provided evidence of new clinical applicability of famotidine for the treatment of demyelinating diseases for which there is currently no effective therapy.

General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain.

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

Iron deficiency in astrocytes alters cellular status and impacts on oligodendrocyte differentiation.

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.

Human oligodendrocyte-like cell differentiation is promoted by TSPO-mediated endogenous steroidogenesis.

Mature oligodendrocytes (OLs) arise from oligodendrocyte precursor cells that, in case of demyelination, are recruited at the lesion site to remyelinate the axons and therefore restore the transmission of nerve impulses. It has been widely documented that exogenously administered steroid molecules are potent inducers of myelination. However, little is known about how neurosteroids produced de novo by OLs can impact this process. Here, we employed a human OL precursor cell line to investigate the role of de novo neurosteroidogenesis in the regulation of OLs differentiation, paying particular attention to the 18 kDa Translocator Protein (TSPO) which controls the rate-limiting step of the neurosteroidogenic process. Our results showed that, over the time of OL maturation, the availability of cholesterol, which is the neurosteroidogenesis initial substrate, and key members of the neurosteroidogenic machinery, including TSPO, were upregulated. In addition, OLs differentiation was impaired following neurosteroidogenesis inhibition and TSPO silencing. On the contrary, TSPO pharmacological stimulation promoted neurosteroidogenic function and positively impacted differentiation. Collectively, our results suggest that de novo neurosteroidogenesis is actively involved in the autocrine and paracrine regulation of human OL differentiation. Moreover, since TSPO was able to promote OL differentiation through a positive modulation of the neurosteroid biosynthetic process, it could be exploited as a promising target to tackle demyelinating diseases.

Celastrol inhibits oligodendrocyte and neuron ferroptosis to promote spinal cord injury recovery.

BACKGROUND: Spinal cord injury (SCI) is a traumatic injury to the central nervous system and can cause lipid peroxidation in the spinal cord. Ferroptosis, an iron-dependent programmed cell death, plays a key role in the pathophysiology progression of SCI. Celastrol, a widely used antioxidant drug, has potential therapeutic value for nervous system. PURPOSE: To investigate whether celastrol can be a reliable candidate for ferroptosis inhibitor and the molecular mechanism of celastrol in repairing SCI by inhibiting ferroptosis. METHODS: First, a rat SCI model was constructed, and the recovery of motor function was observed after treatment with celastrol. The regulatory effect of celastrol on ferroptosis pathway Nrf2-xCT-GPX4 was detected by Western blot and immunofluorescence. Finally, the ferroptosis model of neurons and oligodendrocytes was constructed in vitro to further verify the mechanism of inhibiting ferroptosis by celastrol. RESULTS: Our results demonstrated that celastrol promoted the recovery of spinal cord tissue and motor function in SCI rats. Further in vitro and in vivo studies showed that celastrol significantly inhibited ferroptosis in neurons and oligodendrocytes and reduced the accumulation of ROS. Finally, we found that celastrol could inhibit ferroptosis by up-regulating the Nrf2-xCT-GPX4 axis to repair SCI. CONCLUSION: Celastrol effectively inhibits ferroptosis after SCI by upregulating the Nrf2-xCT-GPX4 axis, reducing the production of lipid ROS, protecting the survival of neurons and oligodendrocytes, and improving the functional recovery.

Pervasive environmental chemicals impair oligodendrocyte development.

Exposure to environmental chemicals can impair neurodevelopment, and oligodendrocytes may be particularly vulnerable, as their development extends from gestation into adulthood. However, few environmental chemicals have been assessed for potential risks to oligodendrocytes. Here, using a high-throughput developmental screen in cultured cells, we identified environmental chemicals in two classes that disrupt oligodendrocyte development through distinct mechanisms. Quaternary compounds, ubiquitous in disinfecting agents and personal care products, were potently and selectively cytotoxic to developing oligodendrocytes, whereas organophosphate flame retardants, commonly found in household items such as furniture and electronics, prematurely arrested oligodendrocyte maturation. Chemicals from each class impaired oligodendrocyte development postnatally in mice and in a human 3D organoid model of prenatal cortical development. Analysis of epidemiological data showed that adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified by our screen. This work identifies toxicological vulnerabilities for oligodendrocyte development and highlights the need for deeper scrutiny of these compounds' impacts on human health.

Genetic background modulates the effect of glucocorticoids on proliferation, differentiation and myelin formation of oligodendrocyte lineage cells.

Anxiety disorders are prevalent mental disorders. Their predisposition involves a combination of genetic and environmental risk factors, such as psychosocial stress. Myelin plasticity was recently associated with chronic stress in several mouse models. Furthermore, we found that changes in both myelin thickness and node of Ranvier morphology after chronic social defeat stress are influenced by the genetic background of the mouse strain. To understand cellular and molecular effects of stress-associated myelin plasticity, we established an oligodendrocyte (OL) model consisting of OL primary cell cultures isolated from the C57BL/6NCrl (B6; innately non-anxious and mostly stress-resilient strain) and DBA/2NCrl (D2; innately anxious and mostly stress-susceptible strain) mice. Characterization of naïve cells revealed that D2 cultures contained more pre-myelinating and mature OLs compared with B6 cultures. However, B6 cultures contained more proliferating oligodendrocyte progenitor cells (OPCs) than D2 cultures. Acute exposure to corticosterone, the major stress hormone in mice, reduced OPC proliferation and increased OL maturation and myelin production in D2 cultures compared with vehicle treatment, whereas only OL maturation was reduced in B6 cultures. In contrast, prolonged exposure to the synthetic glucocorticoid dexamethasone reduced OPC proliferation in both D2 and B6 cultures, but only D2 cultures displayed a reduction in OPC differentiation and myelin production. Taken together, our results reveal that genetic factors influence OL sensitivity to glucocorticoids, and this effect is dependent on the cellular maturation stage. Our model provides a novel framework for the identification of cellular and molecular mechanisms underlying stress-associated myelin plasticity.

Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5.

Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies in Rag1-deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects in S1pr5-deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon-myelin unit.

Ceramide kinase knockout ameliorates multiple sclerosis-like behaviors and demyelination in cuprizone-treated mice.

Changes in sphingolipid metabolism regulate and/or alter many cellular functions in the brain. Ceramide, a central molecule of sphingolipid metabolism, is phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK). CerK and C1P were reported to regulate many cellular responses, but their roles in immune-related diseases in vivo have not been well elucidated. Thus, we investigated the effects of CerK knockout on the onset/progression of multiple sclerosis (MS), which is a chronic neurodegenerative disease accompanied by the loss of myelin sheaths in the brain. MS-model mice were prepared using a diet containing the copper chelator cuprizone (CPZ). Treatment of 8-week-old mice with 0.2% CPZ for 8 weeks resulted in motor dysfunction based on the Rota-rod test, and caused the loss of myelin-related proteins (MRPs) in the brain and demyelination in the corpus callosum without affecting synaptophysin levels. CerK knockout, which did not affect developmental changes in MRPs, ameliorated the motor dysfunction, loss of MRPs, and demyelination in the brain in CPZ-treated mice. Loss of tail tonus, another marker of motor dysfunction, was detected at 1 week without demyelination after CPZ treatment in a CerK knockout-independent manner. CPZ-induced loss of tail tonus progressed, specifically in female mice, to 6-8 weeks, and the loss was ameliorated by CerK knockout. Activities of ceramide metabolic enzymes including CerK in the lysates of the brain were not affected by CPZ treatment. Inhibition of CerK as a candidate for MS treatment was discussed.

Gardenia jasminoides J. Ellis extract alleviated white matter damage through promoting the differentiation of oligodendrocyte precursor cells via suppressing neuroinflammation.

Increasing evidence has highlighted the role of white matter damage in the pathology of Alzheimer's disease (AD). Previous research has shown that a mixture of crocin analogues (GJ-4), Gardenia jasminoides J. Ellis extract, improved cognition in several AD mouse models, but the mechanism remains unclear. The aim of the present study was to investigate the effects and underlying mechanisms of GJ-4 on white matter damage. Proteomic analysis and western blotting results suggested that the level of myelin-related proteins, including myelin basic protein (MBP), myelin associated glycoprotein (MAG) and myelin associated oligodendrocyte basic protein (MOBP), was significantly decreased in the brain of PrP-hAßPPswe/PS1ΔE9 (APP/PS1) transgenic mice, and GJ-4 treatment increased the expressions of these proteins. This result revealed that GJ-4 could ameliorate myelin injury, suggesting that this might be a possible mechanism of GJ-4 on cognition. To validate the effects of GJ-4 on myelin, a metabolite of GJ-4, crocetin, which can pass through the blood-brain barrier, was applied in in vitro experiments. A mechanistic study revealed that crocetin significantly promoted the differentiation of primary cultured oligodendrocyte precursor cells to oligodendrocytes through up-regulation of nuclear Ki67 and transcription factor 2 (Olig2). Oligodendrocytes, the myelin-forming cells, have been reported to be lifelong partners of neurons. Therefore, to investigate the effects of crocetin on myelin and neurons, lysophosphatidylcholine (LPC)-treated primary mixed midbrain neuronal/glial culture was used. Immunofluorescence results indicated that crocetin treatment protected neurons and suppressed microglial activation against LPC-induced injury. To further discern the effects of GJ-4 on white matter injury and neuroinflammation, an LPC-induced mouse model was developed. GJ-4 administration increased oligodendrocyte proliferation, differentiation, and myelin repair. The mechanistic study indicated that GJ-4 improved white matter injury through the regulation of neuroinflammatory dysfunction. These data indicated that GJ-4 effectively repaired white matter damage in the LPC-treated mice. Thus, the present study supported GJ-4 as a potential therapeutic agent for AD and white matter related diseases.

Conversion of Human Fibroblasts into Induced Neural Stem Cells by Small Molecules.

Induced neural stem cells (iNSCs) reprogrammed from somatic cells hold great potentials for drug discovery, disease modelling and the treatment of neurological diseases. Although studies have shown that human somatic cells can be converted into iNSCs by introducing transcription factors, these iNSCs are unlikely to be used for clinical application due to the safety concern of using exogenous genes and viral transduction vectors. Here, we report the successful conversion of human fibroblasts into iNSCs using a cocktail of small molecules. Furthermore, our results demonstrate that these human iNSCs (hiNSCs) have similar gene expression profiles to bona fide NSCs, can proliferate, and are capable of differentiating into glial cells and functional neurons. This study collectively describes a novel approach based on small molecules to produce hiNSCs from human fibroblasts, which may be useful for both research and therapeutic purposes.

Oral treatment of 4-methylumbelliferone reduced perineuronal nets and improved recognition memory in mice.

Hyaluronan (HA) is a core constituent of perineuronal nets (PNNs) that surround subpopulations of neurones. The PNNs control synaptic stabilization in both the developing and adult central nervous system, and disruption of PNNs has shown to reactivate neuroplasticity. We investigated the possibility of memory prolongation by attenuating PNN formation using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis. Adult C57BL/6 mice were fed with chow containing 5% (w/w) 4-MU for 6 months, at a dose ~6.7 mg/g/day. The oral administration of 4-MU reduced the glycosaminoglycan level in the brain to 72% and the spinal cord to 50% when compared to the controls. Spontaneous object recognition test (SOR) performed at 2, 3, 6 and 7 months showed a significant increase in SOR score in the 6-months treatment group 24 h after object presentation. The effect however did not persist in the washout group (1-month post treatment). Immunohistochemistry confirmed a reduction of PNNs, with shorter and less arborization of aggrecan staining around dendrites in hippocampus after 6 months of 4-MU treatment. Histopathological examination revealed mild atrophy in articular cartilage but it did not affect the motor performance as demonstrated in rotarod test. In conclusion, systemic oral administration of 4-MU for 6 months reduced PNN formation around neurons and enhanced memory retention in mice. However, the memory enhancement was not sustained despite the reduction of PNNs, possibly due to the lack of memory enhancement training during the washout period. Our results suggest that 4-MU treatment might offer a strategy for PNN modulation in memory enhancement.

Midazolam Exposure Impedes Oligodendrocyte Development via the Translocator Protein and Impairs Myelination in Larval Zebrafish.

Anesthetics are commonly used in various medical procedures. Accumulating evidence suggests that early-life anesthetics exposure in infants and children affects brain development, causing psychiatric and neurological disorders. However, the underlying mechanisms are poorly understood. Using zebrafish larvae as a model, we found that the proliferation and migration of oligodendrocyte progenitor cells (OPCs) were severely impaired by the exposure of midazolam (MDZ), an anesthetic widely used in pediatric surgery and intensive care medicine, leading to a reduction of oligodendroglial lineage cell in the dorsal spinal cord. This defect was mimicked by the bath application of translocator protein (TSPO) agonists and partially rescued by genetic downregulation of TSPO. Cell transplantation experiments showed that requirement of TSPO for MDZ-induced oligodendroglial lineage cell defects is cell-autonomous. Furthermore, transmission electron microscopy and in vivo electrophysiological recording experiments demonstrated that MDZ exposure caused axon hypomyelination and action potential propagation retardation, resulting in delayed behavior initiation. Thus, our findings reveal that MDZ affects oligodendroglial lineage cell development and myelination in young animals, raising the care about its clinic use in infants and children.

Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination.

Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer's disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.

Immunomodifying and neuroprotective effects of noscapine: Implications for multiple sclerosis, neurodegenerative, and psychiatric disorders.

Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.

Traumatic brain injury in the presence of Aß pathology affects neuronal survival, glial activation and autophagy.

Traumatic brain injury (TBI) presents a widespread health problem in the elderly population. In addition to the acute injury, epidemiological studies have observed an increased probability and earlier onset of dementias in the elderly following TBI. However, the underlying mechanisms of the connection between TBI and Alzheimer's disease in the aged brain and potential exacerbating factors is still evolving. The aim of this study was to investigate cellular injury-induced processes in the presence of amyloid ß (Aß) pathology. For this purpose, a co-culture system of cortical stem-cell derived astrocytes, neurons and oligodendrocytes were exposed to Aß42 protofibrils prior to a mechanically induced scratch injury. Cellular responses, including neurodegeneration, glial activation and autophagy was assessed by immunoblotting, immunocytochemistry, ELISA and transmission electron microscopy. Our results demonstrate that the combined burden of Aß exposure and experimental TBI causes a decline in the number of neurons, the differential expression of the key astrocytic markers glial fibrillary acidic protein and S100 calcium-binding protein beta, mitochondrial alterations and prevents the upregulation of autophagy. Our study provides valuable information about the impact of TBI sustained in the presence of Aß deposits and helps to advance the understanding of geriatric TBI on the cellular level.

Partial protective effects of melatonin on developing brain in a rat model of chorioamnionitis.

Melatonin has shown promising neuroprotective effects due to its anti-oxidant, anti-inflammatory and anti-apoptotic properties, making it a candidate drug for translation to humans in conditions that compromise the developing brain. Our study aimed to explore the impact of prenatal melatonin in an inflammatory/infectious context on GABAergic neurons and on oligodendrocytes (OLs), key cells involved in the encephalopathy of prematurity. An inflammatory/infectious agent (LPS, 300 µg/kg) was injected intraperitoneally (i.p.) to pregnant Wistar rats at gestational day 19 and 20. Melatonin (5 mg/kg) was injected i.p. following the same schedule. Immunostainings focusing on GABAergic neurons, OL lineage and myelination were performed on pup brain sections. Melatonin succeeded in preventing the LPS-induced decrease of GABAergic neurons within the retrospenial cortex, and sustainably promoted GABAergic neurons within the dentate gyrus in the inflammatory/infectious context. However, melatonin did not effectively prevent the LPS-induced alterations on OLs and myelination. Therefore, we demonstrated that melatonin partially prevented the deleterious effects of LPS according to the cell type. The timing of exposure related to the cell maturation stage is likely to be critical to achieve an efficient action of melatonin. Furthermore, it can be speculated that melatonin exerts a modest protective effect on extremely preterm infant brains.

Plasticity-Enhancing Effects of Levodopa Treatment after Stroke.

Dopaminergic treatment in combination with rehabilitative training enhances long-term recovery after stroke. However, the underlying mechanisms on structural plasticity are unknown. Here, we show an increased dopaminergic innervation of the ischemic territory during the first week after stroke induced in Wistar rats subjected to transient occlusion of the middle cerebral artery (tMCAO) for 120 min. This response was also found in rats subjected to permanent focal ischemia induced by photothrombosis (PT) and mice subjected to PT or tMCAO. Dopaminergic branches were detected in the infarct core of mice and rats in both stroke models. In addition, the Nogo A pathway was significantly downregulated in rats treated with levodopa (LD) compared to vehicle-treated animals subjected to tMCAO. Specifically, the number of Nogo A positive oligodendrocytes as well as the levels of Nogo A and the Nogo A receptor were significantly downregulated in the peri-infarct area of LD-treated animals, while the number of Oligodendrocyte transcription factor 2 positive cells increased in this region after treatment. In addition, we observed lower protein levels of Growth Associated Protein 43 in the peri-infarct area compared to sham-operated animals without treatment effect. The results provide the first evidence of the plasticity-promoting actions of dopaminergic treatment following stroke.

Role of MAPK ERK1/2 and p38 in the Regulation of Secretory Functions of Different Populations of Neuroglia in Ethanol-Induced Neurodegeneration.

We studied the participation of ERK1/2 and p38 in secretion of neurotrophic growth factors by various types of neuroglia under conditions of in vitro and in vivo modeled ethanol-induced neurodegeneration. The inhibitory role of these protein kinases in the production of neurotrophins by intact astrocytes and the absence of their participation in the regulation of functions of oligodendrocytes and microglial cells were shown. Under conditions of ethanol neurotoxicity, the role of ERK1/2 and p38 in the production of growth factors by glial elements was significantly changed. Neurodegeneration modeled in vitro led to inversion of the role of both protein kinases in the secretion of neurotrophins by astroglia and inhibition of the cytokine-synthesizing function of oligodendrocytes and microglial cells by ERK1/2 and p38. In mice receiving ethanol per os for a long time (as well as in cells in vitro exposed to ethanol), mitogen-activated kinases stimulated the function of astrocytes and inhibited the production of growth factors by microglial cells. At the same time, chronic alcoholization was accompanied by the appearance of the stimulating role of ERK1/2 and p38 in the implementation of the secretory function by oligodendrocytes.