The therapeutic potential of berberine chloride against SARM1-dependent axon degeneration in acrylamide-induced neuropathy.

Chronic acrylamide (ACR) intoxication causes typical pathology of axon degeneration. Moreover, sterile-α and toll/interleukin 1 receptor motif-containing protein 1 (SARM1), the central executioner of the programmed axonal destruction process under various insults, is up-regulated in ACR neuropathy. However, it remains unclear whether inhibitors targeting SARM1 are effective or not. Among all the pharmacological antagonists, berberine chloride (BBE), a natural phytochemical and the first identified non-competitive inhibitor of SARM1, attracts tremendous attention. Here, we observed the protection of 100 µM BBE against ACR-induced neurites injury (2 mM ACR, 24 hr) in vitro, and further evaluated the neuroprotective effect of BBE (100 mg/kg p.o. three times a week for 4 weeks) in ACR-intoxicated rats (40 mg/kg i.p. three times a week for 4 weeks). The expression of SARM1 was also detected. BBE intervention significantly inhibited the overexpression of SARM1, ameliorated axonal degeneration, alleviated pathological changes in the sciatic nerve and spinal cord, and improved neurobehavioral symptoms in ACR-poisoned rats. Thus, BBE exhibits a strong neuroprotective effect against the SARM1-dependent axon destruction in ACR neuropathy. Meanwhile, our study underscores the need for appropriate inhibitor selection in diverse situations that would benefit from blocking the SARM1-dependent axonal destruction pathway.

Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons.

Wallerian degeneration (WD) is a conserved axonal self-destruction program implicated in several neurological diseases. WD is driven by the degradation of the NAD+ synthesizing enzyme NMNAT2, the buildup of its substrate NMN, and the activation of the NAD+ degrading SARM1, eventually leading to axonal fragmentation. The regulation and amenability of these events to therapeutic interventions remain unclear. Here we explored pharmacological strategies that modulate NMN and NAD+ metabolism, namely the inhibition of the NMN-synthesizing enzyme NAMPT, activation of the nicotinic acid riboside (NaR) salvage pathway and inhibition of the NMNAT2-degrading DLK MAPK pathway in an axotomy model in vitro. Results show that NAMPT and DLK inhibition cause a significant but time-dependent delay of WD. These time-dependent effects are related to NMNAT2 degradation and changes in NMN and NAD+ levels. Supplementation of NAMPT inhibition with NaR has an enhanced effect that does not depend on timing of intervention and leads to robust protection up to 4 days. Additional DLK inhibition extends this even further to 6 days. Metabolite analyses reveal complex effects indicating that NAMPT and MAPK inhibition act by reducing NMN levels, ameliorating NAD+ loss and suppressing SARM1 activity. Finally, the axonal NAD+/NMN ratio is highly predictive of cADPR levels, extending previous cell-free evidence on the allosteric regulation of SARM1. Our findings establish a window of axon protection extending several hours following injury. Moreover, we show prolonged protection by mixed treatments combining MAPK and NAMPT inhibition that proceed via complex effects on NAD+ metabolism and inhibition of SARM1.

Emerging evidence for compromised axonal bioenergetics and axoglial metabolic coupling as drivers of neurodegeneration.

Impaired bioenergetic capacity of the nervous system is thought to contribute to the pathogenesis of many neurodegenerative diseases (NDD). Since neuronal synapses are believed to be the major energy consumers in the nervous system, synaptic derangements resulting from energy deficits have been suggested to play a central role for the development of many of these disorders. However, long axons constitute the largest compartment of the neuronal network, require large amounts of energy, are metabolically and structurally highly vulnerable, and undergo early injurious stresses in many NDD. These stresses likely impose additional energy demands for continuous adaptations and repair processes, and may eventually overwhelm axonal maintenance mechanisms. Indeed, pathological axon degeneration (pAxD) is now recognized as an etiological focus in a wide array of NDD associated with bioenergetic abnormalities. In this paper I first discuss the recognition that a simple experimental model for pAxD is regulated by an auto-destruction program that exhausts distressed axons energetically. Provision of the energy substrate pyruvate robustly counteracts this axonal breakdown. Importantly, energy decline in axons is not only a consequence but also an initiator of this program. This opens the intriguing possibility that axon dysfunction and pAxD can be suppressed by preemptively energizing distressed axons. Second, I focus on the emerging concept that axons communicate energetically with their flanking glia. This axoglial metabolic coupling can help offset the axonal energy decline that activates the pAxD program but also jeopardize axon integrity as a result of perturbed glial metabolism. Third, I present compelling evidence that abnormal axonal energetics and compromised axoglial metabolic coupling accompany the activation of the pAxD auto-destruction pathway in models of glaucoma, a widespread neurodegenerative condition with pathogenic overlap to other common NDD. In conclusion, I propose a novel conceptual framework suggesting that therapeutic interventions focused on bioenergetic support of the nervous system should also address axons and their metabolic interactions with glia.

CEBPß regulation of endogenous IGF-1 in adult sensory neurons can be mobilized to overcome diabetes-induced deficits in bioenergetics and axonal outgrowth.

Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBPß, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBPß overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBPß can be a promising therapeutic approach.

Of axons that struggle to make ends meet: Linking axonal bioenergetic failure to programmed axon degeneration.

Axons are the long, fragile, and energy-hungry projections of neurons that are challenging to sustain. Together with their associated glia, they form the bulk of the neuronal network. Pathological axon degeneration (pAxD) is a driver of irreversible neurological disability in a host of neurodegenerative conditions. Halting pAxD is therefore an attractive therapeutic strategy. Here we review recent work demonstrating that pAxD is regulated by an auto-destruction program that revolves around axonal bioenergetics. We then focus on the emerging concept that axonal and glial energy metabolism are intertwined. We anticipate that these discoveries will encourage the pursuit of new treatment strategies for neurodegeneration.

Changes in serum neurofilament light chain levels following narrowband ultraviolet B phototherapy in clinically isolated syndrome.

OBJECTIVE: To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB-PT). METHODS: sNfL levels were measured using a sensitive single-molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB-PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes. RESULTS: Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7-161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2-212.2) than in HC (10.7 pg/ml [IQR] 4.9-21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB-PT in the first 3 months (UVB-PT -10.6% vs non-UVB-PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall. CONCLUSIONS: Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro-axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB-PT.

[Advance in mechanisms of glial scarring after stroke and intervention of traditional Chinese medicine].

When ischemia or hemorrhagic stroke occurs, astrocytes are activated by a variety of endogenous regulatory factors to become reactive astrocytes. Subsequently, reactive astrocytes proliferate, differentiate, and migrate around the lesion to form glial scar with the participation of microglia, neuron-glial antigen 2(NG2) glial cells, and extracellular matrix. The role of glial scars at different stages of stroke injury is different. At the middle and late stages of the injury, the secreted chondroitin sulfate proteoglycan and chondroitin sulfate are the main blockers of axon regeneration and nerve function recovery. Targeted regulation of glial scars is an important pathway for neurological rehabilitation after stroke. Chinese medicine has been verified to be effective in stroke rehabilitation in clinical practice, possibly because it has the functions of promoting blood resupply, anti-inflammation, anti-oxidative stress, inhibiting cell proliferation and differentiation, and benign intervention in glial scars. This study reviewed the pathological process and signaling mechanisms of glial scarring after stroke, as well as the intervention of traditional Chinese medicine upon glial scar, aiming to provide theoretical reference and research evidence for developing Chinese medicine against stroke in view of targeting glial scarring.

Dopaminergic Receptors as Neuroimmune Mediators in Experimental Autoimmune Encephalomyelitis.

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)-a dopamine D2/D3 receptor-preferring agonist-would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1ß levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.

Trillium tschonoskii rhizomes' saponins induces oligodendrogenesis and axonal reorganization for ischemic stroke recovery in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Trillium tschonoskii Maxim. is one of traditional Chinese medical herbs that has been utilized to treat brain damages and cephalalgia. The neuroprotective effect of total saponins from Trillium tschonoskii rhizome (TSTT) has been demonstrated efficacy in rats following ischemia. However, the axonal remodeling effect of TSTT and the detailed mechanisms after ischemic stroke have not been investigated. AIM OF THE STUDY: We aimed to estimate therapeutic role of TSTT in axonal remodeling using magnetic resonance imaging (MRI) technique, and explored possible mechanisms underlying this process followed by histological assays in ischemic rats. METHODS: Male Sprague-Dawley (SD) rats underwent permanently focal cerebral ischemia induced by occluding right permanent middle cerebral artery. TSTT was intragastrically administrated 6 h after surgery and once daily for consecutive 15 days. Neurological function was assessed by the motor deficit score and beam walking test. T2 relaxation mapping and diffusion tensor imaging (DTI) were applied for detecting cerebral tissues damages and microstructural integrity of axons. Luxol fast blue (LFB) and transmission electron microscope (TEM) were performed to evaluate histopathology in myelinated axons. Double immunofluorescent staining was conducted to assess oligodendrogenesis. Furthermore, the protein expressions regarding to axonal remodeling related signaling pathways were detected by Western blot assays. RESULTS: TSTT treatment (65, 33 mg/kg) markedly improved motor function after ischemic stroke. T2 mapping MRI demonstrated that TSTT decreased lesion volumes, and DTI further confirmed that TSTT preserved axonal microstructure of the sensorimotor cortex and internal capsule. Meanwhile, diffusion tensor tractography (DTT) showed that TSTT elevated correspondent density and length of fiber in the internal capsule. These MRI measurements were confirmed by histological examinations. Notably, TSTT significantly increased Ki67/NG2, Ki67/CNPase double-labeled cells along the boundary zone of ischemic cortex and striatum. Meanwhile, TSTT treatment up-regulated the phosphorylation level of Ser 9 in GSK-3ß, and down-regulated phosphorylated ß-catenin and CRMP-2 expression. CONCLUSION: Taken together, our findings indicated that TSTT (65, 33 mg/kg) enhanced post-stroke functional recovery, amplified endogenous oligodendrogenesis and promoted axonal regeneration. The beneficial role of TSTT might be correlated with GSK-3/ß-catenin/CRMP-2 modulating axonal reorganization after ischemic stroke.

Higher n-3 Polyunsaturated Fatty Acid Diet Improves Long-Term Neuropathological and Functional Outcome after Repeated Mild Traumatic Brain Injury.

Repeated mild traumatic brain injury (TBI) can cause persistent neuropathological effects and is a major risk factor for chronic traumatic encephalopathy. PUFAs (n-3 polyunsaturated fatty acids) were shown to improve acute TBI outcomes in single-injury models in most cases. In this study, we demonstrate positive effects of dietary n-3 PUFA on long-term neuropathological and functional outcome in a clinically relevant model of repeated mild TBI using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Adult mice, reared on n-3 PUFA adequate (higher n-3 PUFA) or deficient (lower n-3 PUFA) diets, were given a mild CHIMERA daily for 3 consecutive days. At 2 months after injury, visual function and spatial memory were evaluated. Glia cell activation was assessed by immunostaining using antibodies of ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein, and axonal damage was examined using silver staining. Repeated CHIMERA (rCHIMERA)-induced gliosis was significantly suppressed in the optic tract, corpus callosum, and hippocampus of mice fed the n-3 PUFA adequate diet compared to the deficient diet group. Considerable axonal damage was detected in the optic tract after rCHIMERA, but the adequate diet group displayed less axonal damage compared to the deficient diet group. rCHIMERA induced a drastic reduction in N1 amplitude of the visual evoked potential in both diet groups and the a-wave amplitude of the electroretinogram in the deficient diet group. However, reduction of N1 and a-wave amplitude were less severe in the adequate diet group. The Morris water maze probe test indicated a significant decrease in the number of platform crossings in the deficient diet group compared to the adequate group. In summary, dietary n-3 PUFA can attenuate persistent glial cell activation and axonal damage and improve deficits in visual function and spatial memory after repeated mild TBI. These data support the neuroprotective potential of a higher n-3 PUFA diet in ameliorating the adverse outcome of repeated mild TBI.

Macrostructural Changes of the Acoustic Radiation in Humans with Hearing Loss and Tinnitus Revealed with Fixel-Based Analysis.

Age-related hearing loss is the most prevalent sensory impairment in the older adult population and is related to noise-induced damage or age-related deterioration of the peripheral auditory system. Hearing loss may affect the central auditory pathway in the brain, which is a continuation of the peripheral auditory system located in the ear. A debilitating symptom that frequently co-occurs with hearing loss is tinnitus. Strikingly, investigations into the impact of acquired hearing loss, with and without tinnitus, on the human central auditory pathway are sparse. This study used diffusion-weighted imaging (DWI) to investigate changes in the largest central auditory tract, the acoustic radiation, related to hearing loss and tinnitus. Participants with hearing loss, with and without tinnitus, and a control group were included. Both conventional diffusion tensor analysis and higher-order fixel-based analysis were applied. The fixel-based analysis was used as a novel framework providing insight into the axonal density and macrostructural morphologic changes of the acoustic radiation in hearing loss and tinnitus. The results show tinnitus-related atrophy of the left acoustic radiation near the medial geniculate body. This finding may reflect a decrease in myelination of the auditory pathway, instigated by more profound peripheral deafferentation or reflecting a preexisting marker of tinnitus vulnerability. Furthermore, age was negatively correlated with the axonal density in the bilateral acoustic radiation. This loss of fiber density with age may contribute to poorer speech understanding observed in older adults.SIGNIFICANCE STATEMENT Age-related hearing loss is the most prevalent sensory impairment in the older adult population. Older individuals are subject to the cumulative effects of aging and noise exposure on the auditory system. A debilitating symptom that frequently co-occurs with hearing loss is tinnitus: the perception of a phantom sound. In this large DWI-study, we provide evidence that in hearing loss, the additional presence of tinnitus is related to degradation of the acoustic radiation. Additionally, older age was related to axonal loss in the acoustic radiation. It appears that older adults have the aggravating circumstances of age, hearing loss, and tinnitus on central auditory processing, which may partly be because of the observed deterioration of the acoustic radiation with age.

Advance in mechanisms of glial scarring after stroke and intervention of traditional Chinese medicine / 中国中药杂志

When ischemia or hemorrhagic stroke occurs, astrocytes are activated by a variety of endogenous regulatory factors to become reactive astrocytes. Subsequently, reactive astrocytes proliferate, differentiate, and migrate around the lesion to form glial scar with the participation of microglia, neuron-glial antigen 2(NG2) glial cells, and extracellular matrix. The role of glial scars at different stages of stroke injury is different. At the middle and late stages of the injury, the secreted chondroitin sulfate proteoglycan and chondroitin sulfate are the main blockers of axon regeneration and nerve function recovery. Targeted regulation of glial scars is an important pathway for neurological rehabilitation after stroke. Chinese medicine has been verified to be effective in stroke rehabilitation in clinical practice, possibly because it has the functions of promoting blood resupply, anti-inflammation, anti-oxidative stress, inhibiting cell proliferation and differentiation, and benign intervention in glial scars. This study reviewed the pathological process and signaling mechanisms of glial scarring after stroke, as well as the intervention of traditional Chinese medicine upon glial scar, aiming to provide theoretical reference and research evidence for developing Chinese medicine against stroke in view of targeting glial scarring.

Investigations on a polyherbal formulation for treatment of cognitive impairment in a cholinergic dysfunctional rodent model.

Alzheimer's disease is a multifactorial neurodegenerative condition manifested through acute cognitive decline, amyloid plaque deposits and neurofibrillary tangles. Complete cure for this disease remains elusive as the conventional drugs address only a single molecular target while Alzheimer's disease involves a complex interplay of different sets of molecular targets and signaling networks. In this context, the possibility of employing multi-drug combinations to rescue neurons from the dysregulated metabolic changes is being actively investigated. The present work investigates a poly-herbal formulation, Brahmi Nei that has been traditionally used for anxiolytic disorders and immunomodulatory effects, for its efficiency in ameliorating cognitive decline through a combination of behavioral, biochemical, histopathological, gene and protein expression analyses. Our results reveal that the formulation shows excellent neuroregenerative properties, rescues neurons from inflammatory damage, reduces neuritic plaque deposits and improves working memory in rodent models with scopolamine-induced dementia. The microarray analysis shows that the formulation induces the expression of pro-survival pathways and positively modulates genes involved in memory consolidation, axonal growth and proliferation in a concentration-dependent manner with therapeutic concentrations restoring the normal conditions in the brain of the diseased animals. The neuritic spine morphology confirms the long-term memory potentiation through improved mushroom spine density, increased dendritic length and connectivity. Taken together, our study provides mechanistic evidence to prove that the traditional formulation can be a superior therapeutic strategy to treat cognitive decline when compared to the conventional mono-drug treatment.

Regulation of degenerative spheroids after injury.

Neuronal injury leads to rapid, programmed disintegration of axons distal to the site of lesion. Much like other forms of axon degeneration (e.g. developmental pruning, toxic insult from neurodegenerative disorder), Wallerian degeneration associated with injury is preceded by spheroid formation along axons. The mechanisms by which injury leads to formation of spheroids and whether these spheroids have a functional role in degeneration remain elusive. Here, using neonatal mouse primary sympathetic neurons, we investigate the roles of players previously implicated in the progression of Wallerian degeneration in injury-induced spheroid formation. We find that intra-axonal calcium flux is accompanied by actin-Rho dependent growth of calcium rich axonal spheroids that eventually rupture, releasing material to the extracellular space prior to catastrophic axon degeneration. Importantly, after injury, Sarm1-/- and DR6-/-, but not Wlds (excess NAD+) neurons, are capable of forming spheroids that eventually rupture, releasing their contents to the extracellular space to promote degeneration. Supplementation of exogenous NAD+ or expressing WLDs suppresses Rho-dependent spheroid formation and degeneration in response to injury. Moreover, injured or trophically deprived Sarm1-/- and DR6-/-, but not Wlds neurons, are resistant to degeneration induced by conditioned media collected from wild-type axons after spheroid rupture. Taken together, these findings place Rho-actin and NAD+ upstream of spheroid formation and may suggest that other mediators of degeneration, such as DR6 and SARM1, mediate post-spheroid rupture events that lead to catastrophic axon disassembly.

Proteomics-Guided Study on Buyang Huanwu Decoction for Its Neuroprotective and Neurogenic Mechanisms for Transient Ischemic Stroke: Involvements of EGFR/PI3K/Akt/Bad/14-3-3 and Jak2/Stat3/Cyclin D1 Signaling Cascades.

Buyang Huanwu Decoction (BHD), a classic traditional Chinese medicine (TCM) formula, has been used for recovering neurological dysfunctions and treating post-stroke disability in China for 200 years. In the present study, we investigated the effects of BHD on inhibiting neuronal apoptosis, promoting proliferation and differentiation of neural stem cells (NSCs) and neurite formation and enhancing learning and memory functional recovery in an experimental rat ischemic stroke model. BHD significantly reduced infarct volume and decreased cell apoptosis in the ischemic brain. BHD enhanced neuronal cell viability in vitro. BHD dose-dependently promoted the proliferation of NSCs in ischemic rat brains in vivo. Moreover, BHD promoted neuronal and astrocyte differentiation in primary cultured NSCs in vitro. Water maze test revealed that BHD promoted the recovery of learning function but not memory functions in the transient ischemic rats. We then investigated the changes of the cellular signaling molecules by using two-dimension (2D) gel electrophoresis and focused on the PI3K/Akt/Bad and Jak2/Stat3/cyclin D1signaling pathway to uncover its underlying mechanisms for its neuroprotective and neurogenetic effects. BHD significantly upregulated the expression of p-PI3K, p-Akt, and p-Bad as well as the expression of p-Jak, p-Stat3, and cyclin D1 in vitro and in vivo. In addition, BHD upregulated Hes1 and downregulated cav-1 in vitro and in vivo. Taken together, these results suggest that BHD has neuroprotective effects and neurogenesis-promoting effects via activating PI3K/Akt/Bad and Jak2/Stat3/Cyclin D1 signaling pathways. Graphical Abstract Buyang Huanwu Decoction (BHD) activates the PI3K-AKT-BAD pathway in the ischemic brain for neuroprotection. BHD also activates JAK2/STAT3/Cyclin D1 signaling cascades for promoting neurogenesis in the hippocampus of post-ischemic brains. Moreover, BHD inhibits the expression of caveolin-1 and increases the expression of HES1 for promoting neuronal differentiation. The neuroprotective and neurogenesis-promoting effects in the hippocampus of post-ischemic brains promote learning ability.

Dietary influence on central nervous system myelin production, injury, and regeneration.

Oligodendrocytes not only produce myelin to facilitate nerve impulse conduction, but are also essential metabolic partners of the axon. Oligodendrocyte loss and myelin destruction, as occurs in multiple sclerosis (MS), leaves axons vulnerable to degeneration and permanent neurological deficits ensue. Many studies now propose that lifestyle factors such as diet may impact demyelinating conditions, including MS. Most prior reviews have focused on the regulatory role of diet in the inflammatory events that drive MS pathogenesis, however the potential for dietary factors to modulate oligodendrocyte biology, myelin injury and myelin regeneration remain poorly understood. Here we review the current evidence from clinical and animal model studies regarding the impact of diet or dietary factors on myelin integrity and other pathogenic features of MS. Some limited evidence exists that certain foods may decrease risk or influence the progression of MS, such as increased intake of fish or polyunsaturated fatty acids, caloric restriction and fasting-mimicking diets. In addition, evidence suggests adolescent obesity or insufficient vitamin D levels increase the risk for developing MS. However, no clear or consistent evidence exists that dietary components exacerbate disease progression. Cumulatively, current evidence highlights the need for more extensive clinical trials to validate dietary effects on MS and to identify diets or supplements that may be beneficial as food-based strategies in the management of MS alone or in combination with conventional disease modifying therapies.

Centella asiatica (L.)-Neurodifferentiated Mesenchymal Stem Cells Promote the Regeneration of Peripheral Nerve.

BACKGROUND: Centella asiatica (L.) is a plant with neuroprotective and neuroregenerative properties; however, its effects on the neurodifferentiation of mesenchymal stem cells (MSCs) and on peripheral nerve injury are poorly explored. This study aimed to investigate the effects of C. asiatica (L.)-neurodifferentiated MSCs on the regeneration of peripheral nerve in a critical-size defect animal model. METHODS: Nerve conduit was developed using decellularised artery seeded with C. asiatica-neurodifferentiated MSCs (ndMSCs). A 1.5 cm sciatic nerve injury in Sprague-Dawley rat was bridged with reversed autograft (RA) (n = 3, the gold standard treatment), MSC-seeded conduit (MC) (n = 4) or ndMSC-seeded conduit (NC) (n = 4). Pinch test and nerve conduction study were performed every 2 weeks for a total of 12 weeks. At the 12th week, the conduits were examined by histology and transmission electron microscopy. RESULTS: NC implantation improved the rats' sensory sensitivity in a similar manner to RA. At the 12th week, nerve conduction velocity was the highest in NC compared with that of RA and MC. Axonal regeneration was enhanced in NC and RA as shown by the expression of myelin basic protein (MBP). The average number of myelinated axons was significantly higher in NC than in MC but significantly lower than in RA. The myelin sheath thickness was higher in NC than in MC but lower than in RA. CONCLUSION: NC showed promising effects on nerve regeneration and functional restoration similar to those of RA. These findings revealed the neuroregenerative properties of C. asiatica and its potential as an alternative strategy for the treatment of critical size nerve defect.

Microglial depletion under thalamic hemorrhage ameliorates mechanical allodynia and suppresses aberrant axonal sprouting.

Central poststroke pain (CPSP) is one of the neuropathic pain syndromes that can occur following stroke involving the somatosensory system. However, the underlying mechanism of CPSP remains largely unknown. Here, we established a CPSP mouse model by inducing a focal hemorrhage in the thalamic ventrobasal complex and confirmed the development of mechanical allodynia. In this model, microglial activation was observed in the somatosensory cortex, as well as in the injured thalamus. By using a CSF1 receptor inhibitor, we showed that microglial depletion effectively prevented allodynia development in our CPSP model. In the critical phase of allodynia development, c-fos-positive neurons increased in the somatosensory cortex, accompanied by ectopic axonal sprouting of the thalamocortical projection. Furthermore, microglial ablation attenuated both neuronal hyperactivity in the somatosensory cortex and circuit reorganization. These findings suggest that microglia play a crucial role in the development of CPSP pathophysiology by promoting sensory circuit reorganization.

Electrophysiological, functional and histopathological assessments of high dose melatonin on regeneration after blunt sciatic nerve injury.

The aim of this study was to determine the curative effects of high-dose (100 mg/kg) melatonin on peripheral nerve injury. Forty male Wistar albino rats were randomized into four groups as sham, vehicle, melatonin, and ischemia and their right sciatic nerves were exposed. The process was terminated in the sham group. In the other groups, nerve injury was induced by clip compression. The vehicle group was intraperitoneally administered ethanol 0.1 cc (melatonin solvent), while the melatonin group was intraperitoneally administered a single dose of melatonin (100 mg/kg). Following the surgery, sciatic nerve functional index (SFI) was measured using walking track analysis on days 7, 14, and 21, and latency, amplitude, and muscle action potentials (MAP) field values were measured using electroneuromyography (ENMG) on day 21. Histopathologically, edema, axonal degeneration, myelin damage, and inflammatory response were evaluated in all groups. SFI values were noted to be statistically significantly different among the vehicle, melatonin, and ischemia groups, and the melatonin group showed a faster recovery. In the ENMG evaluations, higher amplitude and field values in the melatonin group indicated that melatonin accelerated peripheral nerve recovery. Histopathologically, although fibers with loss of myelin were identified in the melatonin group, the myelin sheath was preserved in general and the axonal structure was noted to be normal. A single injection of high-dose melatonin was found to preserve myelin sheath, prevent axonal loss, and accelerate functional recovery during the nerve regeneration in peripheral nerve injury.

Ancestral Folate Promotes Neuronal Regeneration in Serial Generations of Progeny.

Folate supplementation in F0 mating rodents increases regeneration of injured spinal axons in vivo in 4 or more generations of progeny (F1-F4) in the absence of interval folate administration to the progeny. Transmission of the enhanced regeneration phenotype to untreated progeny parallels axonal growth in neuron culture after in vivo folate administration to the F0 ancestors alone, in correlation with differential patterns of genomic DNA methylation and RNA transcription in treated lineages. Enhanced axonal regeneration phenotypes are observed with diverse folate preparations and routes of administration, in outbred and inbred rodent strains, and in two rodent genera comprising rats and mice, and are reversed in F4-F5 progeny by pretreatment with DNA demethylating agents prior to phenotyping. Uniform transmission of the enhanced regeneration phenotype to progeny together with differential patterns of DNA methylation and RNA expression is consistent with a non-Mendelian mechanism. The capacity of an essential nutritional co-factor to induce a beneficial transgenerational phenotype in untreated offspring carries broad implications for the diagnosis, prevention, and treatment of inborn and acquired disorders.