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1.
Int J Biol Sci ; 16(1): 116-134, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31892850

RESUMO

Peripheral nerve injury is a complex condition with a variety of signs and symptoms such as numbness, tingling, jabbing, throbbing, burning or sharp pain. Peripheral nerves are fragile in nature and can easily get damaged due to acute compression or trauma which may lead to the sensory and motor functions deficits and even lifelong disability. After lesion, the neuronal cell body becomes disconnected from the axon's distal portion to the injury site leading to the axonal degeneration and dismantlement of neuromuscular junctions of targeted muscles. In spite of extensive research on this aspect, complete functional recovery still remains a challenge to be resolved. This review highlights detailed pathophysiological events after an injury to a peripheral nerve and the associated factors that can either hinder or promote the regenerative machinery. In addition, it throws light on the available therapeutic strategies including supporting therapies, surgical and non-surgical interventions to ameliorate the axonal regeneration, neuronal survival, and reinnervation of peripheral targets. Despite the availability of various treatment options, we are still lacking the optimal treatments for a perfect and complete functional regain. The need for the present age is to discover or design such potent compounds that would be able to execute the complete functional retrieval. In this regard, plant-derived compounds are getting more attention and several recent reports validate their remedial effects. A plethora of plants and plant-derived phytochemicals have been suggested with curative effects against a number of diseases in general and neuronal injury in particular. They can be a ray of hope for the suffering individuals.

2.
Brain Sci ; 8(9)2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30223579

RESUMO

Regeneration refers to regrowth of tissue in the central nervous system. It includes generation of new neurons, glia, myelin, and synapses, as well as the regaining of essential functions: sensory, motor, emotional and cognitive abilities. Unfortunately, regeneration within the nervous system is very slow compared to other body systems. This relative slowness is attributed to increased vulnerability to irreversible cellular insults and the loss of function due to the very long lifespan of neurons, the stretch of cells and cytoplasm over several dozens of inches throughout the body, insufficiency of the tissue-level waste removal system, and minimal neural cell proliferation/self-renewal capacity. In this context, the current review summarized the most common features of major neurodegenerative disorders; their causes and consequences and proposed novel therapeutic approaches.

3.
Sci Rep ; 8(1): 2246, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396480

RESUMO

Prolonged intake of excessive amounts of ethanol is known to have adverse effects on the central nervous system (CNS). Here we investigated the effects of acute and chronic ethanol exposure and withdrawal from chronic ethanol exposure on glymphatic function, which is a brain-wide metabolite clearance system connected to the peripheral lymphatic system. Acute and chronic exposure to 1.5 g/kg (binge level) ethanol dramatically suppressed glymphatic function in awake mice. Chronic exposure to 1.5 g/kg ethanol increased GFAP expression and induced mislocation of the astrocyte-specific water channel aquaporin 4 (AQP4), but decreased the levels of several cytokines. Surprisingly, glymphatic function increased in mice treated with 0.5 g/kg (low dose) ethanol following acute exposure, as well as after one month of chronic exposure. Low doses of chronic ethanol intake were associated with a significant decrease in GFAP expression, with little change in the cytokine profile compared with the saline group. These observations suggest that ethanol has a J-shaped effect on the glymphatic system whereby low doses of ethanol increase glymphatic function. Conversely, chronic 1.5 g/kg ethanol intake induced reactive gliosis and perturbed glymphatic function, which possibly may contribute to the higher risk of dementia observed in heavy drinkers.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Alcoolismo/patologia , Etanol/administração & dosagem , Etanol/farmacologia , Sistema Glinfático/efeitos dos fármacos , Animais , Aquaporina 4/efeitos dos fármacos , Citocinas/sangue , Demência/induzido quimicamente , Gliose/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sono/fisiologia
4.
PLoS Genet ; 13(11): e1007049, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29107990

RESUMO

The oligodendrocyte density is greater and myelin sheaths are thicker in the adult male mouse brain when compared with females. Here, we show that these sex differences emerge during the first 10 postnatal days, precisely at a stage when a late wave of oligodendrocyte progenitor cells arises and starts differentiating. Androgen levels, analyzed by gas chromatography/tandem-mass spectrometry, were higher in males than in females during this period. Treating male pups with flutamide, an androgen receptor (AR) antagonist, or female pups with 5α-dihydrotestosterone (5α-DHT), revealed the importance of postnatal androgens in masculinizing myelin and their persistent effect into adulthood. A key role of the brain AR in establishing the sexual phenotype of myelin was demonstrated by its conditional deletion. Our results uncover a new persistent effect of postnatal AR signaling, with implications for neurodevelopmental disorders and sex differences in multiple sclerosis.


Assuntos
Androgênios/fisiologia , Encéfalo/efeitos dos fármacos , Bainha de Mielina/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Diferenciação Sexual , Antagonistas de Receptores de Andrógenos/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/fisiologia , Di-Hidrotestosterona/farmacologia , Feminino , Flutamida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/fisiologia
5.
Brain Behav Immun ; 65: 111-124, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28559011

RESUMO

Protein tyrosine phosphatases (PTPs) play essential roles in regulating signaling events in multiple cells by tyrosine dephosphorylation. One of them, PTPσ, appears important in regulating function of plasmacytoid dendritic cells (pDC). Here we report that PTPσ deletion in knockout mice and inhibition with a selective antagonist peptide exacerbated symptoms of experimental autoimmune encephalomyelitis (EAE) by enhancing axon and myelin damage in the spinal cord. PTPσ-/- mice displayed pro-inflammatory profiles in the spinal cord and lymphoid organs following MOG peptide immunization. PTPσ deletion promoted a pro-inflammatory phenotype in conventional DCs and directly regulated differentiation of CD4+ T cells. It also facilitated infiltration of T lymphocytes, activation of macrophages in the CNS and development of EAE. Therefore, PTPσ is a key negative regulator in EAE initiation and progression, which acts by regulating functions of DCs, T cells, and other immune cells. PTPσ may become an important molecular target for treating autoimmune disorders.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/fisiologia , Animais , Diferenciação Celular , Citocinas/metabolismo , Células Dendríticas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/fisiopatologia , Ativação Linfocitária , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Bainha de Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Medula Espinal/metabolismo , Linfócitos T/imunologia
6.
J Neurosci ; 37(2): 397-412, 2017 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-28077718

RESUMO

During development, oligodendrocytes are initially specified, after which oligodendrocyte precursor cells (OPCs) migrate and proliferate before differentiating into myelinating cells. Lineage-specific programming of oligodendrocytes results from sensing environmental cues through membrane-bound receptors and related intracellular signaling molecules. Integrin-linked kinase (ILK) is an important protein that is expressed at the inner margins of the plasma membrane and can mediate some of these signals. The current studies demonstrate that ILK deletion reduces the proliferation and differentiation of OPCs in the developing CNS. There was a significant decrease in the number of OPCs and mature oligodendrocytes throughout postnatal development in Olig1Cre+/- × ILKfl/fl mice. These changes were accompanied by reduced numbers of myelinated axons. Key proteins involved in cell cycle regulation were dysregulated. Cyclin D1/D3 and cyclin-dependent kinase 2/4 (cdc2/cdc4) were downregulated and the cell cycle inhibitor protein p27 Kip1 was upregulated. Therefore, ILK deletion impaired the developmental profile, proliferation, and differentiation of OPCs by altering the expression of regulatory cytoplasmic and nuclear factors. SIGNIFICANCE STATEMENT: Integrin-linked kinase (ILK) is a scaffolding protein involved in integrating signals from the extracellular environment and communicating those signals to downstream effectors within cells. It has been proposed to regulate aspects of oligodendrocyte process extension and thereby myelination. However, the current studies demonstrate that it has an earlier impact on cells in this lineage. Knocking down ILK in Olig1-Cre-expressing cells reduces the pool of oligodendrocyte progenitor cells (OPCs). This smaller pool of OPCs results from altered cell cycle and reduced cell proliferation. These cells myelinate fewer axons than in wild-type mice and, in corpus callosum, the myelin is thinner than in controls. Interestingly, the smaller pool of spinal cord oligodendrocytes generates myelin that is of normal thickness.


Assuntos
Ciclo Celular/fisiologia , Deleção de Genes , Oligodendroglia/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ratos
7.
Brain ; 136(Pt 1): 132-46, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23365095

RESUMO

Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic testosterone analogue 7α-methyl-19-nortestosterone, which has been developed for long-term male contraception and androgen replacement therapy in hypogonadal males and does not stimulate prostate growth, also efficiently promoted myelin repair. These data establish the efficacy of androgens as remyelinating agents and qualify the brain androgen receptor as a promising drug target for remyelination therapy, thus providing the preclinical rationale for a novel therapeutic use of androgens in males with multiple sclerosis.


Assuntos
Encéfalo/metabolismo , Doenças Desmielinizantes/metabolismo , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Receptores Androgênicos/metabolismo , Androgênios/farmacologia , Androgênios/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cuprizona , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/tratamento farmacológico , Doenças Desmielinizantes/patologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/patologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Receptores Androgênicos/genética , Testosterona/farmacologia , Testosterona/uso terapêutico
8.
Front Neurosci ; 6: 10, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22347156

RESUMO

Progesterone is well known as a female reproductive hormone and in particular for its role in uterine receptivity, implantation, and the maintenance of pregnancy. However, neuroendocrine research over the past decades has established that progesterone has multiple functions beyond reproduction. Within the nervous system, its neuromodulatory and neuroprotective effects are much studied. Although progesterone has been shown to also promote myelin repair, its influence and that of other steroids on myelination and remyelination is relatively neglected. Reasons for this are that hormonal influences are still not considered as a central problem by most myelin biologists, and that neuroendocrinologists are not sufficiently concerned with the importance of myelin in neuron functions and viability. The effects of progesterone in the nervous system involve a variety of signaling mechanisms. The identification of the classical intracellular progesterone receptors as therapeutic targets for myelin repair suggests new health benefits for synthetic progestins, specifically designed for contraceptive use and hormone replacement therapies. There are also major advantages to use natural progesterone in neuroprotective and myelin repair strategies, because progesterone is converted to biologically active metabolites in nervous tissues and interacts with multiple target proteins. The delivery of progesterone however represents a challenge because of its first-pass metabolism in digestive tract and liver. Recently, the intranasal route of progesterone administration has received attention for easy and efficient targeting of the brain. Progesterone in the brain is derived from the steroidogenic endocrine glands or from local synthesis by neural cells. Stimulating the formation of endogenous progesterone is currently explored as an alternative strategy for neuroprotection, axonal regeneration, and myelin repair.

9.
Endocrinology ; 152(10): 3820-31, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21828184

RESUMO

Enhancing the endogenous capacity of myelin repair is a major therapeutic challenge in demyelinating diseases such as multiple sclerosis. We found that progesterone and the synthetic 19-norprogesterone derivative 16-methylene-17α-acetoxy-19-norpregn-4-ene-3,20-dione (Nestorone) promote the remyelination of axons by oligodendrocytes after lysolecithin-induced demyelination in organotypic cultures of cerebellar slices taken from postnatal rats or mice. The intracellular progesterone receptors (PR) mediate the proremyelinating actions of Nestorone, because they are not observed in slices from PR knockout mice. Notably, Nestorone was less efficient in heterozygous mice, expressing reduced levels of PR, suggesting PR haploinsufficiency in myelin repair. Using mice expressing the enhanced green fluorescent protein (EGFP) under the control of the proteolipid gene promoter, we showed that both progesterone and Nestorone strongly increased the reappearance of cells of the oligodendroglial lineage in the demyelinated slices. In contrast to Nestorone, the pregnane derivative medroxyprogesterone acetate had no effect. The increase in oligodendroglial cells by Nestorone resulted from enhanced NG2(+) and Olig2(+) oligodendrocyte progenitor cell (OPC) recruitment. In cocultures of lysolecithin-demyelinated cerebellar slices from wild-type mice apposed to brain stem slices of proteolipid gene promoter-EGFP mice, Nestorone stimulated the migration of OPC towards demyelinated axons. In this coculture paradigm, Nestorone indeed markedly increased the number of EGFP(+) cells migrating into the demyelinated cerebellar slices. Our results show that Nestorone stimulates the recruitment and maturation of OPC, two steps which are limiting for efficient myelin repair. They may thus open new perspectives for the use of progestins, which selectively target PR, to promote the endogenous regeneration of myelin.


Assuntos
Axônios/efeitos dos fármacos , Bainha de Mielina/efeitos dos fármacos , Norprogesteronas/farmacologia , Progesterona/farmacologia , Receptores de Progesterona/fisiologia , Animais , Axônios/fisiologia , Movimento Celular/efeitos dos fármacos , Masculino , Acetato de Medroxiprogesterona/farmacologia , Bainha de Mielina/fisiologia , Oligodendroglia/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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