Electroacupuncture suppresses neuronal ferroptosis to relieve chronic neuropathic pain.

Growing evidence supports the analgesic efficacy of electroacupuncture (EA) in managing chronic neuropathic pain (NP) in both patients and NP models induced by peripheral nerve injury. However, the underlying mechanisms remain incompletely understood. Ferroptosis, a novel form of programmed cell death, has been found to be activated during NP development, while EA has shown potential in promoting neurological recovery following acute cerebral injury by targeting ferroptosis. In this study, to investigate the detailed mechanism underlying EA intervention on NP, male Sprague-Dawley rats with chronic constriction injury (CCI)-induced NP model received EA treatment at acupoints ST36 and GV20 for 14 days. Results demonstrated that EA effectively attenuated CCI-induced pain hypersensitivity and mitigated neuron damage and loss in the spinal cord of NP rats. Moreover, EA reversed the oxidative stress-mediated spinal ferroptosis phenotype by upregulating reduced expression of xCT, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH1) and superoxide dismutase (SOD) levels, and downregulating increased expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), malondialdehyde levels and iron overload. Furthermore, EA increased the immunofluorescence co-staining of GPX4 in neurons cells of the spinal cord of CCI rats. Mechanistic analysis unveiled that the inhibition of antioxidant pathway of Nrf2 signalling via its specific inhibitor, ML385, significantly countered EA's protective effect against neuronal ferroptosis in NP rats while marginally diminishing its analgesic effect. These findings suggest that EA treatment at acupoints ST36 and GV20 may protect against NP by inhibiting neuronal ferroptosis in the spinal cord, partially through the activation of Nrf2 signalling.

Focal ischemic stroke modifies microglia-derived exosomal miRNAs: potential role of mir-212-5p in neuronal protection and functional recovery.

BACKGROUND: Ischemic stroke is a severe type of stroke with high disability and mortality rates. In recent years, microglial exosome-derived miRNAs have been shown to be promising candidates for the treatment of ischemic brain injury and exert neuroprotective effects. Mechanisms underlying miRNA dysregulation in ischemic stroke are still being explored. Here, we aimed to verify whether miRNAs derived from exosomes exert effects on functional recovery. METHODS: MiR-212-5p agomir was employed to upregulate miR-212-5p expression in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) as well as an oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Western blot analysis, qRT-PCR and immunofluorescence staining and other methods were applied to explore the underlying mechanisms of action of miR-212-5p. RESULTS: The results of our study found that intervention with miR-212-5p agomir effectively decreased infarct volume and restored motor function in MCAO/R rats. Mechanistically, miR-212-5p agomir significantly reduced the expression of PlexinA2 (PLXNA2). Additionally, the results obtained in vitro were similar to those achieved in vivo. CONCLUSION: In conclusion, the present study indicated that PLXNA2 may be a target gene of miR-212-5p, and miR-212-5p has great potential as a target for the treatment and diagnosis of ischemic stroke.

Pre-treatment of rapamycin transformed M2 microglia alleviates traumatic cervical spinal cord injury via AIM2 signaling pathway in vitro and in vivo.

BACKGROUND: Traumatic spinal cord injury (SCI) is still devastating. It was suggested that the inhibition of mTOR may alleviate neuronal inflammatory injury but its underlying mechanism remained to be elucidated. AIM2 (absent in melanoma 2) recruits ASC (apoptosis-associated speck-like protein containing a CARD) and caspase-1 to form the AIM2 inflammasome, activate caspase-1, and elicit inflammatory responses. We designed this study to elucidate whether pre-treatments of rapamycin could suppress SCI induced neuronal inflammatory injury via AIM2 signaling pathway in vitro and in vivo. METHODS: We performed oxygen and glucose deprivation / re-oxygenation (OGD) treatment and rats clipping model to mimic neuronal injury after SCI in vitro and in vivo. Morphologic changes of injured spinal cord were detected by hematoxylin and eosin staining. The expression of mTOR, p-mTOR, AIM2, ASC, Caspase-1 and et al were analyzed by fluorescent staining, western blotting or qPCR. The polarization phenotype of microglia was identified by flow cytometry or fluorescent staining. RESULTS: We found BV-2 microglia without any pre-treatment cannot alleviate primary cultured neuronal OGD injury. However, pre-treated rapamycin in BV-2 cells could transform microglia to M2 phenotype and protects against neuronal OGD injury via AIM2 signaling pathway. Similarly, pre-treatment of rapamycin could improve the outcome of cervical SCI rats through AIM2 signaling pathway. CONCLUSIONS: It was suggested that resting state microglia pre-treated by rapamycin could protect against neuronal injury via AIM2 signaling pathway in vitro and in vivo. Pre-inhibition of mTOR pathway may improve neuronal protection after SCI.

Maresin1 can be a potential therapeutic target for nerve injury.

Nerve injury significantly affects human motor and sensory function due to destruction of the integrity of nerve structure. In the wake of nerve injury, glial cells are activated, and synaptic integrity is destroyed, causing inflammation and pain hypersensitivity. Maresin1, an omega-3 fatty acid, is a derivative of docosahexaenoic acid. It has showed beneficial effects in several animal models of central and peripheral nerve injuries. In this review, we summarize the anti-inflammatory, neuroprotective and pain hypersensitivity effects of maresin1 in nerve injury and provide a theoretical basis for the clinical treatment of nerve injury using maresin1.

Brain Hypothermia Therapy and Targeted Temperature Management for Acute Encephalopathy in Children: Status and Prospects.

In adult intensive care, brain hypothermia therapy (BHT) was reported to be effective in neuroprotection after resuscitation and cardiac arrest. By contrast, in neonatal intensive care, the pathophysiology of brain damage caused by hypoxic-ischemic encephalopathy (HIE) is attributed to circulatory disturbances resulting from ischemia/reperfusion, for which neonatal brain cryotherapy is used. The International Liaison Committee on Resuscitation, 2010, recommends cerebral cryotherapy for HIE associated with severe neonatal pseudoparenchyma death. The usefulness of BHT for neuroprotection in infants and children, especially in pediatric acute encephalopathy, is expected. Theoretically, BHT could be useful in basic medical science and animal experiments. However, there are limitations in clinical planning for treating pediatric acute encephalopathy. No international collaborative study has been conducted, and no clinical evidence exists for neuroprotection using BHT. In this review, we will discuss the pathogenesis of neuronal damage in hypoxic and hypoperfused brains; the history of BHT, its effects, and mechanisms of action; the success of BHT; cooling and monitoring methods of BHT; adverse reactions to BHT; literature on BHT. We will review the latest literature on targeted temperature management, which is used for maintaining and controlling body temperature in adults in intensive care. Finally, we will discuss the development of BHT and targeted temperature management as treatments for pediatric acute encephalopathy.

MicroRNAs: protective regulators for neuron growth and development.

MicroRNAs (miRNAs) play an important regulatory role in neuronal growth and development. Different miRNAs target different genes to protect neurons in different ways, such as by avoiding apoptosis, preventing degeneration mediated by conditional mediators, preventing neuronal loss, weakening certain neurotoxic mechanisms, avoiding damage to neurons, and reducing inflammatory damage to them. The high expression of miRNAs in the brain has significantly facilitated their development as protective targets for therapy, including neuroprotection and neuronal recovery. miRNA is indispensable to the growth and development of neurons, and in turn, is beneficial for the development of the brain and checking the progression of various diseases of the nervous system. It can thus be used as an important therapeutic target for models of various diseases. This review provides an introduction to the protective effects of miRNA on neurons in case of different diseases or damage models, and then provides reference values and reflections on the relevant treatments for the benefit of future research in the area.

The Roles of Ciliary Neurotrophic Factor - from Neuronutrition to Energy Metabolism.

Ciliary neurotrophic factor (CNTF) is a pluripotent neurotrophic factor originally isolated from chicken embryo ciliary neurons. It has a powerful role in developing and maintaining the optic nervous system and has been used for many vision-related diseases. It also plays an important role in the neurogenesis, regeneration and survival of other neurons, including neural stem cells, dorsal root ganglion, sensory neurons and motor neurons. CNTF is related to neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. In addition to its role in the nervous system, CNTF regulates the balance of energy metabolism and the administration of CNTF induces body weight loss. More CNTF functions have been found with the deepening of study, such as protecting and promoting cardiomyocyte proliferation. In addition, CNTF even participates in mental illness and inflammation suppressing. CNTF exerts multidirectional physiological activity by regulating the transcription of various genes through a variety of signalling pathways (including JAK/STAT, MAPK, and PI3K/AKT). This review summarizes the roles and mechanisms of CNTF in the optic nervous system, retinal-related diseases, neuronal protection, and especially nutrition, energy metabolism and other aspects.

Tetanus Toxin Fragment C: Structure, Drug Discovery Research and Production.

Tetanus toxoid (TTd) plays an important role in the pharmaceutical world, especially in vaccines. The toxoid is obtained after formaldehyde treatment of the tetanus toxin. In parallel, current emphasis in the drug discovery field is put on producing well-defined and safer drugs, explaining the interest in finding new alternative proteins. The tetanus toxin fragment C (TTFC) has been extensively studied both as a neuroprotective agent for central nervous system disorders owing to its neuronal properties and as a carrier protein in vaccines. Indeed, it is derived from a part of the tetanus toxin and, as such, retains its immunogenic properties without being toxic. Moreover, this fragment has been well characterized, and its entire structure is known. Here, we propose a systematic review of TTFC by providing information about its structural features, its properties and its methods of production. We also describe the large uses of TTFC in the field of drug discovery. TTFC can therefore be considered as an attractive alternative to TTd and remarkably offers a wide range of uses, including as a carrier, delivery vector, conjugate, booster, inducer, and neuroprotector.

Cryptotanshinone Attenuates Amyloid-ß42-induced Tau Phosphorylation by Regulating PI3K/Akt/GSK3ß Pathway in HT22 Cells.

The pathological characteristics of Alzheimer's disease (AD) include formation of senile plaques resulting from amyloid-ß (Aß) deposition and neurofibrillary tangles caused by tau hyperphosphorylation. Reducing tau hyperphosphorylation is crucial for treatment of AD. Network pharmacology analysis showed that CTS may reduce tau hyperphosphorylation by regulating the phosphatidylinositol 3 kinases/protein kinase B/ glycogen synthase kinase-3ß (PI3K/Akt/GSK3ß) pathway. We investigated the ability of cryptotanshinone (CTS) to reduce Aß-induced tau hyperphosphorylation and characterized the underlying mechanisms. Amyloid-ß42 oligomers (AßO) were used to establish an AD model in HT22 cells. The expression levels of tau and related proteins in PI3K/Akt/GSK3ß pathway were measured using western blot and immunofluorescence staining. The above-mentioned proteins were then evaluated in an okadaic acid (OKA)-induced AD cell model to verify the results. Synapse-associated proteins including post-synaptic density protein-95 (PSD95) and synaptophysin were also evaluated. We found that CTS significantly reduced tau hyperphosphorylation at Ser202, Ser404, Thr181, and Thr231 in AßO- and OKA-induced cell models. Moreover, we also found that CTS reversed AßO-induced reductions in the levels of PSD95 and synaptophysin. We used LY294002 to block PI3K and the results showed that CTS exerted neuroprotective effects through regulation of the PI3K/Akt/GSK3ß signaling pathway. In summary, we showed for the first time that CTS inhibited AD-related tau hyperphosphorylation and reduced the effects of AßO on the expression levels of PSD95 and synaptophysin via the PI3K/Akt/GSK3ß pathway in HT22 cells.

Carbamate-based N-Substituted tryptamine derivatives as novel pleiotropic molecules for Alzheimer's disease.

A novel series of carbamate-based N-substituted tryptamine derivatives were designed and synthesized based on functional group combination strategy, and possessed both cholinesterase inhibition and neuroprotective effects. After systematically evaluating the cholinesterase inhibitory activity of 24 synthesized compounds, compound 6H6, bearing n-heptyl residue as carbamate moiety, was highlighted due to its great BChE-selective inhibition (eeAChE IC50 > 100 µM; eqBChE IC50 = 7 nM), neuronal protection, antioxidation and anti-neuroinflammation efficacy. Cytotoxicity and acute toxicity assays confirmed the safety-efficacy profiles of compound 6H6. Besides, pharmacokinetic properties and blood-brain barrier (BBB) permeability of compound 6H6 were favorable and suitable for further study in vivo. The behavioral tests revealed that compound 6H6 could remarkably improve the scop-induced ethological changes and memory impairment, suggesting compound 6H6, as an attractive pleiotropic molecule, had great promise in treating Alzheimer's disease.

Overexpression of miR-132-3p contributes to neuronal protection in in vitro and in vivo models of Alzheimer's disease.

One of the neuropathological hallmarks of Alzheimer's disease (AD) is accumulation and deposition of amyloid-beta (Aß1-42) plaques in the hippocampus. Recently, microRNAs (miRNAs), have been demonstrated to play an essential role in AD. We have previously demonstrated that miR-132-3p exerts neuroprotection via regulating histone deacetylase 3 (HDAC3) in a mouse model of AD. In the present study, we further unveiled neuroprotective roles of miR-132-3p in transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mice compared with those in age-matched wild-type C57BL/6 mice. Lentiviral-mediated inhibition or overexpression of miR-132-3p in the hippocampus of APP/PS1 mice was used to explore the contributions of hippocampal miR-132-3p in spatial memory, amyloid burden, apoptosis, and the number of hippocampal cells in a mouse model of AD. Overexpression of hippocampal miR-132-3p ameliorated spatial memory deficits in the Morris water maze, reduced both Aß1-42 accumulation and apoptosis, and promoted the numbers of hippocampal cells in the brains of APP/PS1 mice. Furthermore, trichostatin A (TSA) promoted the expression of miR-132-3p in Aß1-42-burdened neurons while increasing the expression levels of synaptic proteins. Taken together, our results suggest that miR-132-3p may represent a promising therapeutic target for the treatment of AD.

The antidepressant-like effects of Danggui Buxue Decoction in GK rats by activating CREB/BDNF/TrkB signaling pathway.

BACKGROUND: High rates of co-morbidity have been reported in patients with diabetes mellitus with depression (DD). Danggui Buxue Decoction (DBD), a Traditional Chinese Medicine formula composed of Angelica and Astragalus, has been historically used for the treatment of diabetes. PURPOSE: This study aimed to investigated whether DBD and its main active component, ferulic acid (FA) from Angelica, could ameliorate depression-like behavior in DD and the underlying mechanisms. METHODS: Goto-Kakizaki (GK) rats were administered DBD (4 or 8 g/kg) by oral gavage during a 4-week period of chronic unpredictable mild stress. After 4 weeks, blood glucose, glycated serum protein, serum insulin, oral glucose tolerance and depression-like behavior were examined, along with brain-derived neurotrophic factor (BDNF)-related signaling pathway proteins and the ultrastructure of hippocampal tissues. UPLC-QTOF-MS was adopted to detect the absorption of FA in the serum and hippocampus. Rat primary hippocampal cells were cultured in a DD model. Protein and mRNA levels of genes involved in BDNF-related signaling and neuroplasticity were analyzed. RESULTS: DBD effectively improved glucose tolerance in DD rats and relieved depression-like behavior. Upregulation of cAMP response element binding protein (CREB), BDNF, and tropomyosin receptor kinase B (TrkB) and improvement of the hippocampal neuron ultrastructure supported the antidepressant-Like effects of DBD on the hippocampal neurons. In addition, DBD enhanced the protein and mRNA levels of components of the CREB/BDNF/TrkB pathway in rat primary hippocampal cells induced by elevated glycemia and cortisol. Interestingly, FA, the main component of DBD absorbed in the blood and hippocampus, showed similar effects as DBD on primary hippocampal cells. CONCLUSION: This study suggests that the TCM formula DBD effectively serves as a potential therapeutic agent for prevention of DD through regulatory effects on the CREB/BDNF/TrkB pathway to protect and remodel hippocampal neurons. Moreover, FA contributes significantly to the treatment effects of DBD.

Exosomes derived from human induced pluripotent stem cell-derived neural progenitor cells protect neuronal function under ischemic conditions.

Compared with other stem cells, human induced pluripotent stem cells-derived neural progenitor cells (iPSC-NPCs) are more similar to cortical neurons in morphology and immunohistochemistry. Thus, they have greater potential for promoting the survival and growth of neurons and alleviating the proliferation of astrocytes. Transplantation of stem cell exosomes and stem cells themselves have both been shown to effectively repair nerve injury. However, there is no study on the protective effects of exosomes derived from iPSC-NPCs on oxygen and glucose deprived neurons. In this study, we established an oxygen-glucose deprivation model in embryonic cortical neurons of the rat by culturing the neurons in an atmosphere of 95% N2 and 5% CO2 for 1 hour and then treated them with iPSC-NPC-derived exosomes for 30 minutes. Our results showed that iPSC-NPC-derived exosomes increased the survival of oxygen- and glucose-deprived neurons and the level of brain-derived neurotrophic factor in the culture medium. Additionally, it attenuated oxygen and glucose deprivation-induced changes in the expression of the PTEN/AKT signaling pathway as well as synaptic plasticity-related proteins in the neurons. Further, it increased the length of the longest neurite in the oxygen- and glucose-deprived neurons. These findings validate the hypothesis that exosomes from iPSC-NPCs exhibit a neuroprotective effect on oxygen- and glucose-deprived neurons by regulating the PTEN/AKT signaling pathway and neurite outgrowth. This study was approved by the Animal Ethics Committee of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China (approval No. SRRSH20191010) on October 10, 2019.

Glial Cell Line-Derived Neurotrophic Factor and Focal Ischemic Stroke.

Focal ischemic stroke (FIS) is a leading cause of human debilitation and death. Following the onset of a FIS, the brain experiences a series of spatiotemporal changes which are exemplified in different pathological processes. One prominent feature of FIS is the development of reactive astrogliosis and glial scar formation in the peri-infarct region (PIR). During the subacute phase, astrocytes in PIR are activated, referred to as reactive astrocytes (RAs), exhibit changes in morphology (hypotrophy), show an increased proliferation capacity, and altered gene expression profile, a phenomenon known as reactive astrogliosis. Subsequently, the morphology of RAs remains stable, and proliferation starts to decline together with the formation of glial scars. Reactive astrogliosis and glial scar formation eventually cause substantial tissue remodeling and changes in permanent structure around the PIR. Glial cell line-derived neurotrophic factor (GDNF) was originally isolated from a rat glioma cell-line and regarded as a potent survival neurotrophic factor. Under normal conditions, GDNF is expressed in neurons but is upregulated in RAs after FIS. This review briefly describes properties of GDNF, its receptor-mediated signaling pathways, as well as recent studies regarding the role of RAs-derived GDNF in neuronal protection and brain recovery. These results provide evidence suggesting an important role of RA-derived GDNF in intrinsic brain repair and recovery after FIS, and thus targeting GDNF in RAs may be effective for stroke therapy.

Pu'er tea water extract protects against cognitive impairment in a mouse model of lipopolysaccharide-induced neuroinflammation.

BACKGROUND: Pu'er tea, a type of post-fermented tea made from Camellia sinensis leaves, has long been widely used in East Asian countries. It is mainly produced in southern China and is effective in preventing obesity due to its ability to break down fat. However, the effects of Pu'er tea on cognitive impairment or neuroinflammation by endotoxin have not yet been studied. PURPOSE: Here, we assessed the inhibitory activity of Pu'er tea hot water extract (PTW) on neuroinflammation and cognitive impairment and explored its mechanism. STUDY DESIGN: The ability of PTW to inhibit cognitive impairment was investigated in a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation and murine microglia BV2 cells. METHODS: We examined whether oral administration of PTW prevented cognitive impairment and LPS-induced neuroinflammation using behavioral tests, Nissl staining, immunohistochemistry, western blotting, real-time reverse transcription-polymerase chain reaction (real-time RT-PCR), Griess assay, and enzyme-linked immunosorbent assay (ELISA). RESULTS: First, Morris water maze (MWM) and passive avoidance (PA) tests demonstrated that oral administration of PTW effectively attenuated LPS-induced spatial memory loss and inhibited neuronal damage of mouse brains. Histopathological analysis showed that PTW repressed LPS-induced expression of the activation markers ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP). Furthermore, PTW inhibited the expression of amyloidogenesis proteins such as amyloid-ß precursor protein (APP), C99, and ß-secretase-1 (BACE-1); production of inflammatory proteins such as Iba-1, GFAP, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2; activation of inflammatory pathways; and expression of inflammatory mediator mRNAs in hippocampal tissue. In cultured microglia, PTW treatment inhibited the generation of various inflammatory factors activated by LPS. CONCLUSION: Our results in vivo and in vitro demonstrate that PTW effectively prevents cognitive impairment caused by neuroinflammation and is, therefore, a potential candidate for the development of a therapeutic agent for neurodegenerative diseases.

Oxiracetam Offers Neuroprotection by Reducing Amyloid ß-Induced Microglial Activation and Inflammation in Alzheimer's Disease.

Background: Alzheimer's disease (AD) is characterized by amyloid beta (Aß) accumulation in the brain, which triggers the activation of microglia; in turn, microglia release neuroinflammatory factors capable of damaging neurons. Thus, a therapeutic approach targeting this sustained microglia-induced inflammatory response deserves investigation. Here, we examined whether oxiracetam (ORC), a nootropic of the racetam family, can indirectly prevent Aß-induced neurotoxicity by attenuating microglial activation. Methods: Aß42 oligomers were used to stimulate BV2 microglial cells, and the morphological changes and phagocytic capacity of BV2 cells were evaluated using fluorescence microscopy. We used quantitative reverse transcription polymerase chain reaction to assess the inhibitory effects of ORC on Aß-induced mRNA levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α); enzyme-linked immunosorbent assay was used to examine the productions of these cytokines. We also assessed the mRNA level of inducible nitric oxide synthase and the production of nitric oxide (NO). The conditioned medium from BV2 cells was used to culture hippocampal HT22 cells to assess indirect toxicity using the MTT assay. Results: ORC prevented the Aß-induced activation of BV2 cells, as reflected by reduced morphological changes and phagocytic ability. In addition, ORC downregulated the expression of Aß-induced cytokines (IL-1ß, IL-6, and TNF-α) and the production of NO in BV2 cells. Furthermore, ORC protected HT22 cells from indirect damage evoked by Aß-treated BV2 cell-conditioned medium, but not from direct Aß-induced toxicity. Conclusions: ORC suppressed the activation of BV2 cells, decreased the production of Aß-induced inflammatory molecules and NO in BV2 cells, and protected HT22 cells against indirect toxicity mediated by Aß-treated BV2 cell-conditioned medium. Thus, ORC may exert a protective role in AD through attenuating the damage caused by inflammation and oxidative stress.

Banhasasim-Tang Attenuates Lipopolysaccharide-Induced Cognitive Impairment by Suppressing Neuroinflammation in Mice.

Banhasasim-tang (BHS) is an herbal medicine that has been widely used in East Asia to treat various symptoms associated with upper abdomen swelling. BHS has not been studied previously for neuroinflammation or cognitive disorder. Here, we use a lipopolysaccharide (LPS) model to investigate the effects and mechanisms of BHS in neuroinflammation and cognitive impairment of mice. We used a mouse model of LPS-induced cognitive impairment and neuroinflammation and examined whether administration of BHS prevents these deficits via Morris water maze test, passive avoidance test, histopathological analysis, Western blotting, and real-time reverse transcription polymerase chain reaction (RT-qPCR). We found via behavioral tests that BHS treatment effectively prevented LPS-induced memory loss and neuronal damage in mice. Histopathological analysis of mouse brains revealed that BHS inhibited LPS-induced expression of microglial and astrocyte activation markers. Furthermore, BHS inhibits the production of markers related to neurodegeneration, amyloidogenesis, and inflammation, and mRNA expression of inflammatory mediators in mouse brain tissue. Additionally, BHS pretreatment effectively inhibited generation of inflammatory factors and pathways in BV2 microglial cells stimulated by LPS. These observations indicate that BHS is effective in preventing cognitive impairment caused by neuroinflammation and has strong potential as a candidate treatment for neuronal inflammatory diseases.

A balanced evaluation of the evidence for adult neurogenesis in humans: implication for neuropsychiatric disorders.

There is a widespread belief that neurogenesis exists in adult human brain, especially in the dentate gyrus, and it is to be maintained and, if possible, augmented with different stimuli including exercise and certain drugs. Here, we examine the evidence for adult human neurogenesis and note important limitations of the methodologies used to study it. A balanced review of the literature and evaluation of the data indicate that adult neurogenesis in human brain is improbable. In fact, in several high-quality recent studies in adult human brain, unlike in adult brains of other species, neurogenesis was not detectable. These findings suggest that the human brain requires a permanent set of neurons to maintain acquired knowledge for decades, which is essential for complex high cognitive functions unique to humans. Thus, stimulation and/or injection of neural stem cells into human brains may not only disrupt brain homeostatic systems, but also disturb normal neuronal circuits. We propose that the focus of research should be the preservation of brain neurons by prevention of damage, not replacement.

Glia-Like Cells from Late-Passage Human MSCs Protect Against Ischemic Stroke Through IGFBP-4.

Stem cell therapy is considered to be a promising future treatment for intractable neurological diseases, although all the clinical trials using stem cells have not yet shown any good results. Early passage mesenchymal stem cells (MSCs) have been used in most clinical trials because of the issues on safety and efficacy. However, it is not easy to get plenty of cells enough for the treatment and it costs too much. Lots of late passage MSCs can be obtained at lower cost but their efficacy would be a big hurdle for clinical trials. If late passage MSCs with better efficacy could be used in clinical trials, it could be a new and revolutionary solution to reduce cost and enhance easier clinical trials. In the present study, it was investigated whether late passage MSCs could be induced into glia-like cells (ghMSCs); ghMSCs had better efficacy and they protected neurons and the brain from ischemia, and insulin-like growth factor binding protein-4 (IGFBP-4) played a critical role in beneficial effect of ghMSCs. ghMSCs were induced from MSCs and treated in in vitro and in vivo models of ischemia. They effectively protected neurons from ischemia and restored the brain damaged by cerebral infarction. These beneficial effects were significantly blocked by IGFBP-4 antibody. The current study demontsrated that late passage hMSCs can be efficiently induced into ghMSCs with better neuroprotective effect on ischemic stroke. Moreover, the results indicate that IGFBP-4 released from ghMSCs may serve as one of the key neuronal survival factors secreted from ghMSCs.

Oxidative Stress-Tolerant Stem Cells from Human Exfoliated Deciduous Teeth Decrease Hydrogen Peroxide-Induced Damage in Organotypic Brain Slice Cultures from Adult Mice.

Oxidative stress causes severe tissue injury of the central nervous system in ischemic brain damage (IBD), traumatic brain injury (TBI) and neurodegenerative disorders. In this study, we used hydrogen peroxide (H2O2) to induce oxidative stress in organotypic brain slice cultures (OBSCs), and investigated the protective effects of oxidative stress-tolerant (OST) stem cells harvested from human exfoliated deciduous teeth (SHED) which were co-cultivated with OBSCs. Using presto blue assay and immunostaining, we demonstrated that both normal SHED and OST-SHED could prevent H2O2-induced cell death, and increase the numbers of mature neuron and neuronal progenitors in the hippocampus of OBSCs. During co-cultivation, OST-SHED, but not normal SHED, exhibited neuronal cell morphology and expressed neuronal markers. Results from ELISA showed that both normal SHED and OST-SHED significantly decreased oxidative DNA damage in H2O2-treated OBSCs. SHED could also produce neurotrophic factor BDNF (brain derived neurotrophic factor) and promoted the production of IL-6 in OBSCs. Although OST-SHED had lower cell viability, the neuronal protection of OST-SHED was significantly superior to that of normal SHED. Our findings suggest that SHED, especially OST-SHED, could prevent oxidative stress induced brain damage. OST-SHED can be explored as a new therapeutic tool for IBD, TBI and neurodegenerative disorders.