Traumatic brain injury (TBI) causes significant mortality in most developing countries worldwide. At present, it is imperative to identify a treatment to address the devastating post-TBI consequences. Therefore, the present study has been performed to assess the specific effect of immediate exposure to normabaric hyperoxia (NBO) after fluid percussion injury (FPI) in the striatum of mice. To execute FPI, mice were anesthetised and sorted into (i) a TBI group, (ii) a sham group without injury and (iii) a TBI group treated with immediate exposure to NBO for 3 h. Afterwards, brains were harvested for morphological assessment. The results revealed no changes in morphological and neuronal damage in the sham group as compared to the TBI group. Conversely, the TBI group showed severe morphological changes as well as neuronal damage as compared to the TBI group exposed to NBO for 3 h. Interestingly, our findings also suggested that NBO treatment could diminish the neuronal damage in the striatum of mice after FPI. Neuronal damage was evaluated at different points of injury and the neighbouring areas using morphology, neuronal apoptotic cell death and pan-neuronal markers to determine the complete neuronal structure. In conclusion, immediate exposure to NBO following FPI could be a potential therapeutic approach to reduce neuronal damage in the TBI model.
Besides acting as potent free radical scavengers, tocopherols and tocotrienols have been known to have non-antioxidant properties such as the involvement of alpha-tocopherol (alphaT) in PKC pathway and the anti-cancer properties of gamma-tocotrienol (gammaT3). This study aims to elucidate whether protective effects shown by alphaT and gammaT3 in H(2)O(2)-induced neuron cultures have anti-apoptotic or pro-apoptotic tendency toward the initiation of neuronal apoptosis. H(2)O(2) is used to induce apoptosis in primary cerebellar neuron cultures which is attenuated by pretreatment of alphaT or gammaT3 at concentrations < or =10 microM. Similar to our previous work, gammaT3 was found to be neurotoxic at concentrations > or =100 microM, whereas alphaT showed no neurotoxicity. Cellular uptake of gammaT3 was higher than that of alphaT. Treating cells simultaneously with either gammaT3 or alphaT and with then H(2)O(2) led to higher expression of Bax and Bcl-2 than in neurons exposed to H(2)O(2) alone. Analysis of Bcl-2/Bax ratio as 'survival index' showed that both pretreatment of gammaT3 and alphaT followed by H(2)O(2) increase the 'survival index' of Bcl-2/Bax ratio compared to H(2)O(2)-treated cells, while treatment of gammaT3 alone decrease the ratio compared to unchanged Bcl2/Bax ratio of similar treatment with alphaT alone. Similar treatment of gammaT3 decreased p53 expression and activates p38 MAPK phosphorylation, whereas alphaT did not alter its expression compared to H(2)O(2)-treated cells. Treating neurons with only gammaT3 or alphaT increased the expression of Bax, Bcl-2, p53, and p38 MAPK compared to control with gammaT3 exerting stronger expression for proteins involved than alphaT. In conclusion, low doses of gammaT3 and alphaT confer neuroprotection to H(2)O(2)-treated neurons via their antioxidant mechanism but gammaT3 has stronger pro-apoptosis tendency than alphaT by activating molecules involved in the neuronal apoptotic pathway in the absence of H(2)O(2).
Nerve conduction study is essential in the diagnosis of focal neuropathies and diffuse polyneuropathies. There are many factors that can affect nerve conduction velocity, and age is one of them. Most of the many studies of this effect, and the values from them, were on Caucasian subjects. Therefore, this study was designed to investigate the effect of age on conduction velocity among healthy Asian Malay subjects by analyzing its influence on the median, ulnar, and sural nerves.
Matched MeSH terms: Motor Neurons/metabolism; Neurons, Afferent/metabolism
α-Synuclein (α-Syn) plays a crucial role in the pathophysiology of Parkinson's disease (PD). α-Syn has been extensively studied in many neuronal cell-based PD models but has yielded mixed results. The objective of this study was to re-evaluate the dual cytotoxic/protective roles of α-Syn in dopaminergic SH-SY5Y cells. Stable SH-SY5Y cells overexpressing wild type or familial α-Syn mutants (A30P, E46K and A53T) were subjected to acute and chronic rotenone and maneb treatment. Compared with untransfected SH-SY5Y cells, wild type α-Syn attenuated rotenone and maneb-induced cell death along with an attenuation of toxin-induced mitochondrial membrane potential changes and Reactive Oxygen Species level, whereas the mutant α-Syn constructs exacerbated environmental toxins-induced cytotoxicity. After chronic treatment, wild type α-Syn but not the mutant variants was found to rescue cells from subsequent acute hydrogen peroxide insult. These results suggest that the fundamental property of wild type α-Syn may be protective, and such property may be lost by its familial PD mutations.
A growing body of evidence suggests the existence of a functional interaction between gabapentin (GBP)-morphine system. However, the neuro-anatomical sites and molecular mechanism of action of gabapentin-morphine interaction to prevent and reverse morphine side effects as well as enhancement of the analgesic effect of morphine is not clear. Therefore, we examined the combined effects of GBP-morphine on acute morphine-induced c-Fos expression in rat nucleus accumbens. The combined effect of GBP-morphine was examined by means of c-Fos immunohistochemistry. A single intraperitoneal injection (i.p.) of morphine (10 mg/kg), saline (control), and co-injection of GBP (150 mg/kg) with morphine (5 mg/kg) was administered under anesthesia. The deeply anesthetized rats were perfused transcardially with 4% paraformaldehyde 2 h after drugs administration. Serial 40 μm thick sections of brain were cut and processed by immunohistochemistry to locate and quantify the sites and number of neurons with c-Fos immunoreactivity. Detection of c-Fos protein was performed using the peroxidase-antiperoxidase detection protocol. The present study demonstrated that, administration of GBP (150 mg/kg, i.p.) in combination with morphine (5 mg/kg, i.p.) significantly (p < 0.01) attenuated the acute morphine (5 mg/kg, i.p.)-induced c-Fos expression in the rat nucleus accumbens shell. Present results showed that GBP-morphine combination action prevented the acute morphine-induced c-Fos expression in rat nucleus accumbens. Moreover, this study provides first evidence of neuro-anatomical site and that GBP neutralized the morphine-induced activation of rat nucleus accumbens shell.
The vertebrate retina is a clearly organized signal-processing system. It contains more than 60 different types of neurons, arranged in three distinct neural layers. Each cell type is believed to serve unique role(s) in encoding visual information. While we now have a relatively good understanding of the constituent cell types in the retina and some general ideas of their connectivity, with few exceptions, how the retinal circuitry performs computation remains poorly understood. Computational modeling has been commonly used to study the retina from the single cell to the network level. In this article, we begin by reviewing retinal modeling strategies and existing models. We then discuss in detail the significance and limitations of these models, and finally, we provide suggestions for the future development of retinal neural modeling.
Thymoquinone (TQ), a bioactive constituent of Nigella sativa Linn (N. sativa) has demonstrated several neuropharmacological attributes. In the present study, the neuroprotective properties of TQ were investigated by studying its anti-apoptotic potential to diminish β-amyloid peptide 1-40 sequence (Aβ1-40)-induced neuronal cell death in primary cultured cerebellar granule neurons (CGNs). The effects of TQ against Aβ1-40-induced neurotoxicity, morphological damages, DNA condensation, the generation of reactive oxygen species, and caspase-3, -8, and -9 activation were investigated. Pretreatment of CGNs with TQ (0.1 and 1 μM) and subsequent exposure to 10 μM Aβ1-40 protected the CGNs against the neurotoxic effects of the latter. In addition, the CGNs were better preserved with intact cell bodies, extensive neurite networks, a loss of condensed chromatin and less free radical generation than those exposed to Aβ1-40 alone. TQ pretreatment inhibited Aβ1-40-induced apoptosis of CGNs via both extrinsic and intrinsic caspase pathways. Thus, the findings of this study suggest that TQ may prevent neurotoxicity and Aβ1-40-induced apoptosis. TQ is, therefore, worth studying further for its potential to reduce the risks of developing Alzheimer's disease.
Poliovirus (PV) can spread through neural pathway to the central nervous system and replicates in motor neurons, which leads to poliomyelitis. Enterovirus 71 (EV71), which is closely related to PV, is one of the causative agents of hand-foot-and-mouth disease and can cause severe neurological diseases similar to poliomyelitis. Since PV is similar to EV71 in its motor neurotoxicity, we tried to understand if the results obtained with PV are of general applicability to EV71 and other viruses with similar characteristics. Using microfluidic devices, we demonstrated that both PV capsid and the PV genome undergo axonal retrograde transport with human PV receptor (hPVR), and the transported virus replicated in the soma of hPVR-expressing motor neurons. Similar to PV in hPVR-transgenic (Tg) mice, neural pathway ensuring spreading of EV71 has been shown in adult human scavenger receptor class B, member 2 (hSCARB2)-Tg mice. We have validated this finding in microfluidic devices by showing that EV71 is retrogradely transported together with hSCARB2 to the cell body where it replicates in an hSCARB2-dependent manner.
The aim of the study was to investigate the location of motor neuron somata of geniohyoid muscle in rat. Nine Sprague-Dawley rats were used in this study. Operations were performed under general anaesthesia. Nembutal sodium, 40 mg per kg intraperitoneally was used for anaesthesia. 0.02 to 0.05 ml of 30% horseradish peroxidase (Sigma Type VI) solution in normal saline was injected into the exposed right geniohyoid muscle. After 48 hr, the animals were fixed by perfusion through left ventricle of heart, first by 100 ml normal saline and then with 500 ml of 1.25% glutaraldehyde and 1% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4, at room temperature, and finally with 500 ml of 10% sucrose in the same buffer at 4°C. The medulla oblongata and first cervical segment of spinal cord were removed, kept in 10% sucrose in above phosphate buffer at 4°C for 24 hr. Thereafter, their serial transverse sections were cut in a cryostat at a thickness of 60 μm. The sections were treated according to tetramethyl benzidine (TMB)-horseradish peroxidase (HRP) method. HRP-labelled neuron somata were observed at the following sites: (a) In ventral part of right main hypoglossal nucleus in upper two-thirds of the closed part of medulla oblongata. (b) In ventrolateral subnucleus of hypoglossal nucleus in lower third of closed part of medulla oblongata. (c) At spinomedullary junction, they were located in dorsomedial part of right ventral grey column; a few were also seen here scattered on right side of central canal and among corticospinal fibres.
Induced pluripotent stem cells (iPSCs) have great potentials for regenerative medicine. However, serious concerns such as the use of the viral-mediated reprogramming strategies and exposure of iPSCs to animal products from feeder cells and serum-containing medium have restricted the application of iPSCs in the clinics. Therefore, the generation of iPSCs with minimal viral integrations and in non-animal sourced and serum-free medium is necessary. In this report, a polycistronic lentiviral vector carrying Yamanaka's factors was used to reprogram mouse fibroblasts into iPSCs in feeder- and xeno-free culture environment. The generated iPSCs exhibited morphology and self-renewal properties of embryonic stem cells (ESCs), expression of specific pluripotent markers, and potentials to differentiate into the three-major distinct specialized germ layers in vitro. The iPSCs were also shown to have the potential to differentiate into neural precursor and neurons in culture, with greater than 95% expression of nestin, Pax6 and βIII-tubulin. This body of work describes an alternative method of generating iPSCs by using polycistronic lentiviral vector that may minimize the risks associated with viral vector-mediated reprogramming and animal derived products in the culture media.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons. Motor features such as tremor, rigidity, bradykinesia and postural instability are common traits of PD. Current treatment options provide symptomatic relief to the condition but are unable to reverse disease progression. The conventional single-target therapeutic approach might not always induce the desired effect owing to the multifactorial nature of PD. Hence, multitarget strategies have been proposed to simultaneously target multiple proteins involved in the development of PD. Herein, we provide an overview of the pathogenesis of PD and the current pharmacotherapies. Furthermore, rationales and examples of multitarget approaches that have been tested in preclinical trials for the treatment of PD are also discussed.
The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia-neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic ('housekeeping') cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non-neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.
Tobacco smoke is not only a leading cause for chronic obstructive pulmonary disease, cardiovascular disorders, and lung and oral cancers, but also causes neurological disorders such as Alzheimer 's disease. Tobacco smoke consists of more than 4500 toxic chemicals, which form free radicals and can cross blood-brain barrier resulting in oxidative stress, an extracellular amyloid plaque from the aggregation of amyloid β (Aβ) peptide deposition in the brain. Further, respiratory infections such as Chlamydia pneumoniae, respiratory syncytial virus have also been involved in the induction and development of the disease. The necessary information collated on this review has been gathered from various literature published from 1995 to 2019. The review article sheds light on the role of smoking and respiratory infections in causing oxidative stress and neuroinflammation, resulting in Alzheimer's disease (AD). This review will be of interest to scientists and researchers from biological and medical science disciplines, including microbiology, pharmaceutical sciences and the translational researchers, etc. The increasing understanding of the relationship between chronic lung disease and neurological disease is two-fold. First, this would help to identify the risk factors and possible therapeutic interventions to reduce the development and progression of both diseases. Second, this would help to reduce the probable risk of development of AD in the population prone to chronic lung diseases.
Gonadotropin-releasing hormone (GnRH) is a reproductive neuropeptide, which controls vertebrate reproduction. In most vertebrates, there are more than two GnRH orthologs in the brain. In cichlid fish, the Nile tilapia (Oreochromis niloticus), GnRH1 is the primary hypophysiotropic hormone, while GnRH2 and GnRH3 are non-hypophysiotropic but neuromodulatory in function. Hypophysiotropic GnRH neurons are thought to inter-communicate, while it remains unknown if hypophysiotropic and non-hypophysiotropic GnRH systems communicate with each other. In the present study, we examined interrelationship between three GnRH types using specific antibodies raised against their respective GnRH associated peptide (GAP) sequence. Double-immunofluorescence labeling coupled with confocal microscopy revealed that in sexually mature males, GnRH-GAP1-immunoreactive (-ir) processes are in proximities of GnRH-GAP3-ir cell somata in the terminal nerve, while GnRH-GAP1-ir cell somata were also accompanied by GnRH-GAP3-ir processes in the preoptic area. However, such interaction was not seen in immature males. Further, there was no interaction between GnRH-GAP2 and GnRH-GAP1 or GnRH-GAP3 neurons. Single cell gene expression analysis revealed co-expression of multiple GnRH receptor genes (gnrhr1 and gnrhr2) in three GnRH-GAP cell types. In mature males, high levels of gnrhr2 mRNA were expressed in GnRH-GAP1-ir cells. In immature males, gnrhr1 and gnrhr2 mRNAs are highly expressed in GnRH-GAP3-ir cells. These results suggest heterologous interactions between the three GnRH-GAP cell types and their potential functional interaction during different reproductive stages.
One of the strategies in the establishment of in vitro oxidative stress models for neurodegenerative diseases, such as Alzheimer's disease (AD), is to induce neurotoxicity by amyloid beta (Aβ) peptides in suitable neural cells. Presently, data on the neurotoxicity of Aβ in neural cells differentiated from stem cells are limited. In this study, we attempted to induce oxidative stress in transgenic 46C mouse embryonic stem cell-derived neurons via treatment with Aβ peptides (Aβ1-42 and Aβ25-35). 46C neural cells were generated by promoting the formation of multicellular aggregates, embryoid bodies in the absence of leukemia inhibitory factor, followed by the addition of all-trans retinoic acid as the neural inducer. Mature neuronal cells were exposed to different concentrations of Aβ1-42 and Aβ25-35 for 24 h. Morphological changes, cell viability, and intracellular reactive oxygen species (ROS) production were assessed. We found that 100 µM Aβ1-42 and 50 µM Aβ25-35 only promoted 40% and 10%, respectively, of cell injury and death in the 46C-derived neuronal cells. Interestingly, treatment with each of the Aβ peptides resulted in a significant increase of intracellular ROS activity, as compared to untreated neurons. These findings indicate the potential of using neurons derived from stem cells and Aβ peptides in generating oxidative stress for the establishment of an in vitro AD model that could be useful for drug screening and natural product studies.
Extreme stress is closely linked with symptoms of depression. Chronic social stress can cause structural and functional changes in the brain. These changes are associated with dysfunction of neuroprotective signalling that is necessary for cell survival, growth, and maturation. Reduced neuronal numbers and volume of brain regions have been found in depressed patients, which may be caused by decreased cell survival and increased cell death. Elucidating the mechanism underlying the degeneration of the neuroprotective system in social stress-induced depression is important for developing neuroprotective measures. The Repressor Element 1 Silencing Transcription Factor (REST) also known as Neuron-Restrictive Silencing Factor (NRSF) has been reported as a neuroprotective molecule in certain neurological disorders. Decreased expression levels of REST/NRSF in the nucleus can induce death-related gene expression, leading to neuronal death. Under physiological stress conditions, REST/NRSF over expression is known to activate neuronal survival in the brain. Alterations in REST/NRSF expression in the brain has been reported in stressed animal models and in the post-mortem brain of patients with depression. Here, we highlight the neuroprotective function of REST/NRSF and discuss dysregulation of REST/NRSF and neuronal damage during social stress and depression.
Alzheimer's disease (AD) has been clinically characterized by a progressive degeneration of neurons which resulted in a gradual and irreversible cognitive impairment. The accumulation of Aβ and τ proteins in the brain contribute to the severity of the disease. Recently, vitexin compound has been the talk amongst researchers due to its pharmacological properties as anti-inflammation and anti-AD. However, the epigenetic mechanism of the compound in regulating the neuroinflammation activity is yet to be fully elucidated. Hence, this review discusses the potential of vitexin compound to have the pharmacoepigenetic property in regulating the neuroinflammation activity in relation to AD. It is with hope that the review would unveil the potential of vitexin as the candidate in treating AD.
The motoneurones with axons in the common peroneal nerve (CPN) of the rat and monkey were examined using retrograde labelling with horseradish peroxidase (HRP). In both species, the CPN motoneurone pool was localized in the dorsolateral part of the ventral horn of the spinal cord. In the rat, the labelled motoneurones were located between the L3 and L6 spinal segments whereas in the monkey, they extended from the caudal end of L4 to the L6 spinal segments. In both species the majority of the labelled neurones were located within the L5 segment. The mean number of the CPN motoneurones in the rat and monkey was 458 and 1148, respectively. A bimodal size distribution of motoneurones was found in both species.
Injury to neuronal tissues in the central nervous system (CNS) of mammals results in neural degeneration and sometime leads to loss of function, whereas fish retain a remarkable potential for neuro-regeneration throughout life. Thus, understanding the mechanism of neuro-regeneration in fish CNS would be useful to improve the poor neuro-regenerative capability in mammals. In the present study, we characterized a neuro-regenerative process in the brain of a cichlid, tilapia, Oreochromis niloticus. Morphological observations showed that the damaged brain region (habenula) successfully regrew and reinnervated axonal projections by 60 days post-damage. A fluorescent carbocyanine tracer, DiI tracing revealed a recovery of the major neuronal projection from the regenerated habenula to the interpenduncular nucleus by 60 days post-damage. TUNEL assay showed a significant increase of apoptotic cells (~234%, P<0.01) at one day post-damage, while the number of bromodeoxyuridine (BrdU)-positive proliferative cells were significantly increased (~92%, P<0.05) at 7 days post-damage compared with sham-control fish. To demonstrate a potential role of apoptotic activity in the neuro-regeneration, effects of degenerative neural tissue on cell proliferation were examined in vivo. Implantation of detached neural but not non-neural tissues into the cranial cavity significantly (P<0.01) increased the number of BrdU-positive cells nearby the implantation regions at 3 days after the implantation. Furthermore, local injection of the protein extract and cerebrospinal fluid collected from injured fish brain significantly induced cell proliferation in the brain. These results suggest that factor(s) derived from apoptotic neural cells may play a critical role in the neuro-regeneration in teleost brain.
The utilization of zebrafish in biomedical research is very common in the research world nowadays. Today, it has emerged as a favored vertebrate organism for the research in science of reproduction. There is a significant growth in amount numbers of scientific literature pertaining to research discoveries in reproductive sciences in zebrafish. It has implied the importance of zebrafish in this particular field of research. In essence, the current available literature has covered from the very specific brain region or neurons of zebrafish, which are responsible for reproductive regulation, until the gonadal level of the animal. The discoveries and findings have proven that this small animal is sharing a very close/similar reproductive system with mammals. More interestingly, the behavioral characteristics and along with the establishment of animal courtship behavior categorization in zebrafish have laid an even stronger foundation and firmer reason on the suitability of zebrafish utilization in research of reproductive sciences. In view of the immense importance of this small animal for the development of reproductive sciences, this review aimed at compiling and describing the proximate close similarity of reproductive regulation on zebrafish and human along with factors contributing to the infertility, showing its versatility and its potential usage for fertility research.