Valproic acid protects neurons and promotes neuronal regeneration after brachial plexus avulsion

Valproic acid has been shown to exert neuroprotective effects and promote neurite outgrowth in several peripheral nerve injury models. However, whether valproic acid can exert its beneficial effect on neurons after brachial plexus avulsion injury is currently unknown. In this study, brachial plexus root avulsion models, established in Wistar rats, were administered daily with valproic acid dis-solved in drinking water （300 mg/kg） or normal water. On days 1, 2, 3, 7, 14 and 28 after avulsion injury, tissues of the C 5-T 1 spinal cord segments of the avulsion injured side were harvested to in-vestigate the expression of Bcl-2, c-Jun and growth associated protein 43 by real-time PCR and western blot assay. Results showed that valproic acid significantly increased the expression of Bcl-2 and growth associated protein 43, and reduced the c-Jun expression after brachial plexus avulsion. Our findings indicate that valproic acid can protect neurons in the spinal cord and enhance neuronal regeneration fol owing brachial plexus root avulsion.

Co-culture of oligodendrocytes and neurons can be used to assess drugs for axon regeneration in the central nervous system

We present a novel in vitro model in which to investigate the efficacy of experimental drugs for the promotion of axon regeneration in the central nervous system. We co-cultured rat hippocampal neurons and cerebral cortical oligodendrocytes, and tested the co-culture system using a Nogo-66 receptor antagonist peptide（NEP1–40）, which promotes axonal growth. Primary cultured oligodendrocytes suppressed axonal growth in the rat hippocampus, but NEP1–40 stimulated axonal growth in the co-culture system. Our results confirm the validity of the neuron-oligodendrocyte co-culture system as an assay for the evaluation of drugs for axon regeneration in the central nervous system.

Endogenous retinal neural stem cell reprogramming for neuronal regeneration

In humans, optic nerve injuries and associated neurodegenerative diseases are often followed by perma- nent vision loss. Consequently, an important challenge is to develop safe and effective methods to replace retinal neurons and thereby restore neuronal functions and vision. Identifying cellular and molecular mechanisms allowing to replace damaged neurons is a major goal for basic and translational research in regenerative medicine. Contrary to mammals, the zebrafish has the capacity to fully regenerate entire parts of the nervous system, including retina. This regenerative process depends on endogenous retinal neural stem cells, the Miiller glial cells. Following injury, zebrafish Miiller cells go back into cell cycle to proliferate and generate new neurons, while mammalian Mtiller cells undergo reactive gliosis. Recently, transcription factors and microRNAs have been identified to control the formation of new neurons derived from ze- brafish and mammalian Mtiller cells, indicating that cellular reprogramming can be an efficient strategy to regenerate human retinal neurons. Here we discuss recent insights into the use of endogenous neural stem cell reprogramming for neuronal regeneration, differences between zebrafish and mammalian Mtiller cells, and the need to pursue the identification and characterization of new molecular factors with an instructive and potent function in order to develop theurapeutic strategies for eye diseases.

Semaphorin 3A: from growth cone repellent to promoter of neuronal regeneration

Highlight Semaphorin 3A is a classically known axonal guidance cue that mediates axonal growth cone repulsion and collapse.Recent works,however,suggest that it may have the apparently diametrically opposite activity of promoting neuronal regeneration.

Serotonin controls axon and neuronal regeneration in the nervous system:lessons from regenerating animal models

Traumatic brain injury （TBI） is a mechanical injury to brain tissue that leads to an impairment of function and a broad spectrum of symptoms and disabilities; often, it is followed by diffuse axonal injury, which causes denaturation of the white matter and axon retraction, leaving patients with severe brain damage or even in a persistent vegetative state.

The metabolic brain network in patients with Parkinson's disease based on ^(18)F-FDG PET imaging: evaluation of neuronal injury and regeneration

Over the past two decades, the development of functional imaging methods has greatly promoted our understanding on the changes of neurons following neurodegenerative disorders, such as Parkin- son＇s disease （PD）. The application of a spatial covariance analysis on 18F-FDG PET imaging has led to the identification of a distinc- tive disease-related metabolic pattern. This pattern has proven to be useful in clinical diagnosis, disease progression monitoring as well as assessment of the neuronal changes before and after clinical treatment. It may potentially serve as an objective biomarker on disease progression monitoring, assessment, histological and func- tional evaluation of related diseases.

Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease

There is currently no treatment for effectively slowing the progression of Alzheimer＇s disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The present study investigated the effects of myricetin, a member of the flavonoids, on intracerebroventricular streptozotocin induced neuronal loss and memory impairment in rat models of Alzheimer＇s disease. Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 m L/kg saline. Behavioral test（the shuttle box test） was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer＇s disease. These findings suggest that myricetin is beneficial for treatment of Alzheimer＇s disease.

Promoting neuronal regeneration using extracellular vesicles loaded with superparamagnetic iron oxide nanoparticles

Intercellular communication between neurons and glial cells via extracellular vesicles（EVs）as a novel mechanism of information transfer has been shown to be involved in regeneration processes within the central nervous system（CNS）（Rajendran et al.,2014）.Hence,to take advantage of EV signaling for therapeutic applications appears to be a completely new approach to promote regeneration.

Toxic effect of acrylamide on the development of hippocampal neurons of weaning rats

Although numerous studies have examined the neurotoxicity of acrylamide in adult animals,the effects on neuronal development in the embryonic and lactational periods are largely unknown.Thus,we examined the toxicity of acrylamide on neuronal development in the hippocampus of fetal rats during pregnancy.Sprague-Dawley rats were mated with male rats at a 1：1 ratio.Rats were administered 0,5,10 or 20 mg/kg acrylamide intragastrically from embryonic days 6–21.The gait scores were examined in pregnant rats in each group to analyze maternal toxicity.Eight weaning rats from each group were also euthanized on postnatal day 21 for follow-up studies.Nissl staining was used to observe histological change in the hippocampus.Immunohistochemistry was conducted to observe the condition of neurites,including dendrites and axons.Western blot assay was used to measure the expression levels of the specific nerve axon membrane protein,growth associated protein 43,and the presynaptic vesicle membrane specific protein,synaptophysin.The gait scores of gravid rats significantly increased,suggesting that acrylamide induced maternal motor dysfunction.The number of neurons,as well as expression of growth associated protein 43 and synaptophysin,was reduced with increasing acrylamide dose in postnatal day 21 weaning rats.These data suggest that acrylamide exerts dose-dependent toxic effects on the growth and development of hippocampal neurons of weaning rats.

Pulsed electrical stimulation protects neurons in the dorsal root and anterior horn of the spinal cord after peripheral nerve injury

Most studies on peripheral nerve injury have focused on repair at the site of injury, but very few have examined the effects of repair strategies on the more proximal neuronal cell bodies. In this study, an approximately 10-mm-long nerve segment from the ischial tuberosity in the rat was transected and its proximal and distal ends were inverted and sutured. The spinal cord was subjected to pulsed electrical stimulation at T10 and L3, at a current of 6.5 m A and a stimulation frequency of 15 Hz, 15 minutes per session, twice a day for 56 days. After pulsed electrical stimulation, the number of neurons in the dorsal root ganglion and anterior horn was increased in rats with sciatic nerve injury. The number of myelinated nerve fibers was increased in the sciatic nerve. The ultrastructure of neurons in the dorsal root ganglion and spinal cord was noticeably improved. Conduction velocity of the sciatic nerve was also increased. These results show that pulsed electrical stimulation protects sensory neurons in the dorsal root ganglia as well as motor neurons in the anterior horn of the spinal cord after peripheral nerve injury, and that it promotes the regeneration of peripheral nerve fibers.

Calcium channel inhibition-mediated axonal stabilization improves axonal regeneration after optic nerve crush

Axonal projections are specialized neuronal compartments and the longest parts of neurons.Axonal degeneration is a common pathological feature in many neurodegenerative disorders,such as Parkinson’s disease,amyotrophic lateral sclerosis,glaucoma,as well as in traumatic lesions of the central nervous system（CNS）,such as spinal cord injury.

Underlying mechanism of protection from hypoxic injury seen with n-butanol extract of Potentilla anserine L. in hippocampal neurons

The alcohol and n-butanol extract of Potentilla anserine L. significantly protects myocardium from acute ischemic injury. However, its effects on rat hippocampal neurons and the mechanism of protection remain unclear. In this study, primary cultured hippocampal neurons from neonatal rats were incubated in 95% N2 and 5% CO2 for 4 hours. Results indicated that hypoxic injury decreased the viability of neurons, increased the expression levels of caspase-9 and caspase-3 mRNA, as well as cytochrome c, Caspase-9, and Caspase-3 protein. Pretreatment with 0.25, 0.062 5, 0.015 6 mg/mL n-butanol extract of Potentilla anserine L. led to a significant increase in cell viability. Expression levels of caspase-9 and caspase-3 mRNA, as well as cytochrome c, Caspase-9, and Caspase-3 protein, were attenuated. The neuroprotective effect of n-butanol extract of Potentilla anserine L. was equivalent to tanshinone IIA. Our data suggest that the n-butanol extract of Potentilla anserine L. could protect primary hippocampal neurons from hypoxic injury by deactivating mitochondrial cell death.

Cortical regulation of striatal projection neurons and interneurons in a Parkinson's disease rat model

Striatal neurons can be either projection neurons or interneurons, with each type exhibiting distinct susceptibility to various types of brain damage. In this study, 6-hydroxydopamine was injected into the right medial forebrain bundle to induce dopamine depletion, and/or ibotenic acid was injected into the M1 cortex to induce motor cortex lesions. Immunohistochemistry and western blot assay showed that dopaminergic depletion results in significant loss of striatal projection neurons marked by dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein, molecular weight 32 k Da, calbindin, and μ-opioid receptor, while cortical lesions reversed these pathological changes. After dopaminergic deletion, the number of neuropeptide Y-positive striatal interneurons markedly increased, which was also inhibited by cortical lesioning. No noticeable change in the number of parvalbumin-positive interneurons was found in 6-hydroxydopamine-treated rats. Striatal projection neurons and interneurons show different susceptibility to dopaminergic depletion. Further, cortical lesions inhibit striatal dysfunction and damage induced by 6-hydroxydopamine, which provides a new possibility for clinical treatment of Parkinson＇s disease.

Biochemical indicators for neuronal regeneration during intrathecal triamcinolone application in multiple sclerosis

Multiple sclerosis （MS） is a chronic inflammatory disease of the central nervous system （CNS）. Essential charac- teristics are demyelination, inflammation and neurode- generation. This process affects the white and grey matter in the CNS. MS patients experience various progression subtypes in association with the cerebral or spinal, acute inflammatory or glial sclerotic lesions （Mtiller, 2009）. Most patients end up in a progressive, smouldering, chronic inflammatory process （MUller, 2009）. Current predominantly used 1.5 respectively 3 Tesla MRI with Gadolinium~ application visualize the various old and acute lesions. They serve as a biological marker in com- bination with standardised assessment of brain atrophy, black holes, etc. However, MRI with a stronger magnetic 7 Tesla field with better sensitivity gave hints on an on- going, acute inflammatory, smouldering process even with Gadolinium~ enhancing acute lesions in the brain and the spinal cord in progressive, so-called relapse free MS patients （Mtiller, 2009; Sinnecker et al., 2012）. Ad- ditionally, progress of MS is determined with subjective standardised clinical ratings （Sinnecker et al., 2012）. Both methods are used for the evaluation of the efficacy of relapse rate reducing drugs. These compounds, i.e., in- terferons, teriflunamide, glatiramer acetate, fingolimod, fumarate or monoclonal antibodies, preponderantly weaken the malfunction of the peripheral immune system in relapse remitting MS patients. These MS drugs share one common disadvantage. They do not stop progression or improve MS within a framework of a regenerative process. They do not enable reversal of symptoms, for in- stance functional deficits or spasticity （Mtiller, 2009）.

Hippocampal neuronal regeneration after epilepsy

Changes in hippocampal ultrastructure and gene expression of various nerve factors are strongly associated with the pathogenesis of epilepsy during seizure. Recent studies have shown that

(-)-Epigallocatechin-3-gallate protects spiral ganglion neurons against amikacin-induced apoptosis

Morphology of spiral ganglion neurons （SGNs） in Sprague-Dawley rats before and after amikacin treatment was observed by transmission electron microscopy. Amikacin induced cochlear SGN apoptosis. Immunohistochemical staining and RT-PCR revealed a decrease in Bcl-2 protein ex-pression, and an increase in Bax protein, caspase-3 protein and caspase-6 mRNA expression fol-lowing amikacin treatment. （-）-Epigallocatechin-（3）-gallate （EGCG） inhibited SGN Bax protein, caspase-3 protein and caspase-6 mRNA expression, and enhanced Bcl-2 protein expression, thereby decreasing SGN apoptosis. Results demonstrated that EGCG can protect SGNs against amikacin-induced injury.

Role of granulocyte macrophage colony stimulating factor in regeneration of the central nervous system

Traditionally,it has been thought that the mammalian central nervous system（CNS）does not regenerate.Possibly due to the inhibitory extracellular environment post-injury as well as the limited intrinsic characteristics of adult post-mitotic neurons（Smith et al.,2015）.

Activation of hypothalamic gono-like neurons in female rats during estrus

In mammals, gonadal function is controlled by the activity of hypothalamic gonadotropin-releasing hormone neurons, which control the secretion of adenohypophyseal and gonadal hormones. However, there are a number of unanswered questions in relation to gonadal function. It is currently unknown how erotogenic stimulation of the genitals influences the subpopulation of hypothalamic medial preoptic area neurons, antidromically identified as projecting to the median eminence at different periods of the estrous cycle. Additionally, the distinctiveness of hypothalamic medial preoptic area neurons, with respect to methods of feedback control by exogenous hormones, is also unknown. In this study, spontaneous discharges from individual neurons encountered within the medial preoptic area, gono-like neurons, were recorded extracellularly using glass microelectrodes. To confirm the cellular and histochemical properties of the recording units, antidromic stimulation was performed using a side-by-side bipolar stimulating electrode placed into the median eminence, alongside microiontophoretic injections of the conventional tracer, horseradish peroxidase. In addition, further immunohistochemical analyses were performed. Results showed that elevated gono-neuron activity was accompanied by increased background activity and greater responses to erotogenic stimuli during estrus. Application of clitoral traction stimulation resulted in increased activation of the gono-like neurons. This neuronal activity was noticeably inhibited by β-estradiol administration. Immunohistochemical analyses revealed the presence of gonadotropin-releasing hormone-reactive protein in hypothalamic cells in which electrophysiological recordings were taken. Thus, medial preoptic area neurons represent the subset of hypothalamic gonadotropin-releasing hormone neurons described from brain slices in vitro, and might serve as a useful physiological model to form the basis of future in vivo studies.

Dantrolene enhances the protective effect of hypothermia on cerebral cortex neurons

Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is neuroprotective in in vitro and in vivo ischemic injury models. In addition to its neuroprotective effect, dantrolene neutralizes the adverse reaction of hypothermia. Dantrolene may be an effective adjunctive therapy to enhance the neuroprotection of hypothermia in treating ischemic stroke. Cortical neurons isolated from rat fetuses were exposed to 90 minutes of oxygen-glucose deprivation followed by reoxygenation. Neurons were treated with 40 μM dantrolene, hypothermia（at 33°C）, or the combination of both for 12 hours. Results revealed that the combination of dantrolene and hypothermia increased neuronal survival and the mitochondrial membrane potential, and reduced intracellular active oxygen cytoplasmic histone-associated DNA fragmentation, and apoptosis. Furthermore, improvements in cell morphology were observed. The combined treatment enhanced these responses compared with either treatment alone. These findings indicate that dantrolene may be used as an effective adjunctive therapy to enhance the neuroprotective effects of hypothermia in ischemic stroke.

Modification of ubiquitin C-terminal hydrolase L1 by reactive lipid species: role in neural regeneration and diseases of aging

Role of ubiquitin C-terminal hydrolase L1（UCHL1）in brain function：Ubiquitin is used by a variety of cellular systems to tag proteins for transport to various organelles.There are a number of enzymes in the ubiquitin-proteasome pathway（UPP）that tag abnormally folded proteins with ubiquitin for transport to the proteasome for degradation.