Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction. Furthermore, Scriptaid shifted microglia/macrophage polarization toward the protective M2 phenotype and mitigated inflammation. In primary cocultures of microglia and oligodendrocytes, Scriptaid increased expression of microglial glycogen synthase kinase 3 beta (GSK3β), which phosphorylated and inactivated phosphatase and tensin homologue (PTEN), thereby enhancing phosphatidylinositide 3-kinases (PI3K)/Akt signaling and polarizing microglia toward M2. The increase in GSK3β in microglia and their phenotypic switch to M2 was associated with increased preservation of neighboring oligodendrocytes. These findings are consistent with recent findings that microglial phenotypic switching modulates white matter repair and axonal remyelination and highlight a previously unexplored role for HDAC activity in this process. Furthermore, the functions of GSK3β may be more subtle than previously thought, in that GSK3β can modulate microglial functions via the PTEN/PI3K/Akt signaling pathway and preserve white matter homeostasis. Thus, inhibition of HDACs in microglia is a potential future therapy in TBI and other neurological conditions with white matter destruction.

https://www.pnas.org/content/pnas/112/9/2853.full.pdf

HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis

Amyotrophic lateral sclerosis (ALS) involves a complex interaction between genetic susceptibility and environmental insults. In this Review, Paez-Colasante and colleagues discuss various disease mechanisms that might apply to ALS, with particular emphasis on epigenetic factors. To date, only one treatment even modestly improves survival in patients with ALS, and the authors discuss several potential new therapeutic targets.

Amyotrophic lateral sclerosis: Mechanisms and therapeutics in the epigenomic era

ALS: A bucket of genes, environment, metabolism and unknown ingredients.

Introduction. Human neurodegenerative diseases increase progressively with age and present a high social and economic burden. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are both growth factors exerting trophic effects on neuronal regeneration in the central nervous system (CNS) and peripheral nervous system (PNS). GH and IGF-1 stimulate protein synthesis in neurons, glia, oligodendrocytes, and Schwann cells, and favor neuronal survival, inhibiting apoptosis. This study aims to evaluate the effect of GH and IGF-1 on neurons, and their possible therapeutic clinical applications on neuron regeneration in human subjects. Methods. In the literature, we searched the clinical trials and followed up studies in humans, which have evaluated the effect of GH/IGF-1 on CNS and PNS. The following keywords have been used: “GH/IGF-1” associated with “neuroregeneration”, “amyotrophic lateral sclerosis”, “Alzheimer disease”, “Parkinson’s disease”, “brain”, and “neuron”. Results. Of the retrieved articles, we found nine articles about the effect of GH in healthy patients who suffered from traumatic brain injury (TBI), and six studies (four using IGF-1 and two GH therapy) in patients with amyotrophic lateral sclerosis (ALS). The administration of GH in patients after TBI showed a significantly positive recovery of brain and mental function. Treatment with GH and IGF-1 therapy in ALS produced contradictory results. Conclusions. Although strong findings have shown the positive effects of GH/IGF-1 administration on neuroregeneration in animal models, a very limited number of clinical studies have been conducted in humans. GH/IGF-1 therapy had different effects in patients with TBI, evidencing a high recovery of neurons and clinical outcome, while in ALS patients, the results are contradictory. More complex clinical protocols are necessary to evaluate the effect of GH/IGF-1 efficacy in neurodegenerative diseases. It seems evident that GH and IGF-1 therapy favors the optimal recovery of neurons when a consistent residual activity is still present. Furthermore, the effect of GH/IGF-1 could be mediated by, or be overlapped with that of other hormones, such as estradiol and testosterone.

https://www.mdpi.com/1422-0067/18/11/2441/pdf

Neurotrophic and Neuroregenerative Effects of GH/IGF1.

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bpa.12350

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

Motor neuron physiology and development depend on a continuous and tightly regulated trophic support from a variety of cellular sources. Trophic factors guide the generation and positioning of motor neurons during every stage of the developmental process. As well, they are involved in axon guidance and synapse formation. Even in the adult spinal cord an uninterrupted trophic input is required to maintain neuronal functioning and protection from noxious stimuli. Among the trophic factors that have been demonstrated to participate in motor neuron physiology are vascular endothelial growth factor (VEGF), glial-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and insulin-like growth factor 1 (IGF-1). Upon binding to membrane receptors expressed in motor neurons or neighboring glia, these trophic factors activate intracellular signaling pathways that promote cell survival and have protective action on motor neurons, in both in vivo and in vitro models of neuronal degeneration. For these reasons these factors have been considered a promising therapeutic method for amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, although their efficacy in human clinical trials have not yet shown the expected protection. In this review we summarize experimental data on the role of these trophic factors in motor neuron function and survival, as well as their mechanisms of action. We also briefly discuss the potential therapeutic use of the trophic factors and why these therapies may have not been yet successful in the clinical use.

/pdf/trophic-factors-as-modulators-of-motor-neuron-physiology-and-5dhha1ehpr.pdf

Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by the progressive loss of motor neurons. The cause of this selective neuronal death is unknown, but transcriptional dysregulation is recently emerging as an important factor. The physical substrate for the regulation of the transcriptional process is chromatin, a complex assembly of histones and DNA. Histones are subject to several post-translational modifications, like acetylation, that are a component of the transcriptional regulation process. Histone acetylation and deacetylation is performed by a group of enzymes (histone acetyltransferases (HATs) and deacetylases, respectively) whose modulation can alter the transcriptional state of many regions of the genome, and thus may be an important target in diseases that share this pathogenic process, as is the case for ALS. This review will discuss the present evidence of transcriptional dysregulation in ALS, the role of histone deacetylases (HDACs) in disease pathogenesis, and the novel pharmacologic strategies that are being comprehensively studied to prevent motor neuron death, with focus on sirtuins (SIRT) and their effectors.

/pdf/histone-deacetylases-and-their-role-in-motor-neuron-ydr2pd3s0v.pdf

Histone deacetylases and their role in motor neuron degeneration

Spinal inhibitory circuits and their role in motor neuron degeneration.

Excitotoxicity is a mechanism of foremost importance in the selective motor neuron degeneration characteristic of motor neuron disorders. Effective therapeutic strategies are an unmet need for these disorders. Polyphenols, such as quercetin and resveratrol, are plant-derived compounds that activate sirtuins (SIRTs) and have shown promising results in some models of neuronal death, although their effects have been scarcely tested in models of motor neuron degeneration. In this work we investigated the effects of quercetin and resveratrol in an in vivo model of excitotoxic motor neuron death induced by the chronic infusion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the rat spinal cord tissue. Quercetin and resveratrol were co-infused with AMPA and motor behavior and muscle strength were assessed daily for up to ten days. Then, animals were fixed and lumbar spinal cord tissue was analyzed by histological and immunocytological procedures. We found that the chronic infusion of AMPA [1 mM] caused a progressive motor neuron degeneration, accompanied by astrogliosis and microgliosis, and motor deficits and paralysis of the rear limbs. Quercetin infusion ameliorated AMPA-induced paralysis, rescued motor neurons, and prevented both astrogliosis and microgliosis, and these protective effects were prevented by EX527, a very selective SIRT1 inhibitor. In contrast, neither resveratrol nor EX527 alone improved motor behavior deficits or reduced motor neuron degeneration, albeit both reduced gliosis. These results suggest that quercetin exerts its beneficial effects through a SIRT1-mediated mechanism, and thus SIRT1 plays an important role in excitotoxic neurodegeneration and therefore its pharmacological modulation might provide opportunities for therapy in motor neuron disorders.

/pdf/quercetin-prevents-spinal-motor-neuron-degeneration-induced-31nch6ci16.pdf

Quercetin prevents spinal motor neuron degeneration induced by chronic excitotoxic stimulus by a sirtuin 1-dependent mechanism

Motor neuron degeneration is the pathological hallmark of motor neuron diseases, a group of neurodegenerative disorders clinically manifested as muscle fasciculations and hyperreflexia, followed by paralysis, respiratory failure and death. Ample evidence supports a role of glutamate-mediated excitotoxicity in motor death. In previous work we showed that stimulation of glutamate release from nerve endings by perfusion of the K+-channel blocker 4-aminopyridine (4-AP) in the rat hippocampus induces seizures and neurodegeneration, and that AMPA insusion in the spinal cord produces paralysis and motor neuron death. On these bases, in this work we have tested the effect of the chronic infusion of 4-AP in the spinal cord, using implanted osmotic minipumps, on motor activity and on motor neuron survival, and the mechanisms underlying this effect. 4-AP produced muscle fasciculations and motor deficits assessed in two motor tests, which start 2-3 h after the implant, which ameliorated spontaneously within 6-7 days, but no neurodegeneration. These effects were prevented by both AMPA and NMDA receptors blockers. The role of GABAA receptors was also explored, and we found that chronic infusion of bicuculline induced moderate motor neuron degeneration and enhanced the hyperexcitation produced by 4-AP. Unexpectedly, the GABAAR agonist muscimol also induced motor deficits and failed to prevent the MN death induced by AMPA. We conclude that motor alterations induced by chronic 4-AP infusion in the spinal cord in vivo is due to ionotropic glutamate receptor overactivation and that blockade of GABAergic neurotransmission induces motor neuron death under chronic conditions. These results shed light on the role of glutamatergic and GABAergic neurotransmission in the regulation of motor neuron excitability in the spinal cord.

/pdf/motor-alterations-induced-by-chronic-4-aminopyridine-3kvpe0kj5m.pdf

Rafael Lazo-Gómez

Papers

Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy

Histone deacetylases and their role in motor neuron degeneration

Spinal inhibitory circuits and their role in motor neuron degeneration.

Quercetin prevents spinal motor neuron degeneration induced by chronic excitotoxic stimulus by a sirtuin 1-dependent mechanism

Motor Alterations Induced by Chronic 4-Aminopyridine Infusion in the Spinal Cord In vivo: Role of Glutamate and GABA Receptors