Neurotrophin Gene Research Articles

Conditioned Medium Protects Dopaminergic Neurons in Parkinsonian Rats.

Objective Adipose derived stem cells (ASCs) secrete numerous neurotrophic factors and cytokines in conditioned medium (CM), which protect neurons by its antioxidative and trophic effects. This research assesses the neuroprotective effect of ASC- CM on neurotrophins genes expressions and tyrosine hydroxylase positive (TH+) cell density in male Wistar rats lesioned by 6-hydroxydopamine (6-OHDA). Materials and Methods In this experimental study, the groups consisted of lesioned and sham rats with unilateral injections of 20 µg of 6-OHDA neurotoxin and phosphate buffered saline (PBS) into the striatum, respectively. Another groups received intravenous injections of 3×106 cells (ASCs group), 500 µl of CM (ASC-CM group) or medium [α-minimal essential medium (α-MEM) group)]. All rats underwent evaluations with the rotarod and apomorphine-induced rotation tests at 2, 4, 6, and 8 weeks post-injection. At 8 weeks we sacrificed some of the animals for real-time polymerase chain reaction (PCR) analysis, and evaluation of TH+cell counts. Results We observed a significant decrease in contralateral turns to the lesions in the ASCs and ASC-CM groups compared to the neurotoxin lesioned or α-MEM groups at 8 weeks post transplantation. Cell and CM- injected rats showed a significant increase of staying on the rotarod compared to the lesion or α-MEM groups. Cell and CM-treated rats showed significant increases in the NGF and NT3 genes, respectively, compared with the lesion group. Both treated groups showed significant increases in BDNF gene expression and TH+ cell density. ConclusionThe results suggested that ASCs and ASC-CM protected dopaminergic neurons through the expressions of neurotrophin genes.

Erratum to: "Sex Differences in Risk for Alzheimer's Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study".

Neurotrophins, including nerve-growth factor and brain-derived neurotrophic factor, have been implicated in Alzheimer's disease (AD). Associations between AD and neurotrophin signaling genes have been inconsistent, with few studies examining sex differences in risk. We examined four single-nucleotide polymorphisms (SNPs) involved in neurotrophin signaling (rs6265, rs56164415, rs2289656, rs2072446) and risk for AD by sex in a population-based sample of older adults. Three thousand four hundred and ninety-nine individuals without dementia at baseline [mean (standard deviation) age = 74.64 (6.84), 58% female] underwent dementia screening and assessment over four triennial waves. Cox regression was used to examine time to AD or right censoring for each SNP. Female carriers of the minor T allele for rs2072446 and rs56164415 had a 60% (hazard ratio [HR] = 1.60, 95% confidence interval [CI] = 1.02-2.51) and 93% (HR = 1.93, 95% CI = 1.30-2.84) higher hazard for AD, respectively, than male noncarriers of the T allele. Furthermore, male carriers of the T allele of rs2072446 had a 61% lower hazard (HR = 0.39, 95% CI = 0.14-1.06) than male noncarriers at trend-level significance (p = .07). The association between certain neurotrophin gene polymorphisms and AD differs by sex and may explain inconsistent findings in the literature.

Investigation of Spinal nerve Ligation Effect on Muscular Neurotrophin-4 Gene Expression in Male Wistar Rats

Introduction: Motor neurons in spinal cord dictate the structural and contractile properties of muscles. Damage to motor neurons change muscles gene expression pattern. Given that Neurotrophin-4 (NT-4) is required for survival and normal function of muscle fibers, the aim of present study is investigation effect of Decreased activity model as Spinal Nerve Ligation on muscular NT-4 gene expression. Materials & methods: Ten adult male wistar rats in the weight range of 250±20 gr randomly were divided into two groups including healthy control (C), Spinal nerve ligation (SNL). Over the six weeks after SNL, neuropathic pain behavior tests were conducted continually in groups. In the end of Sixth weeks, change of NT-4 gene expression in soleus muscle was measured with Real time technique. Findings: Behavioral tests demonstrated that spinal nerve ligation induce thermal Hyperalgesia and mechanical Allodynia in the SNL group which decreased pain threshold seen in allover period of study (P≤0.05). Also, compared to the C group, NT-4 gene expression in soleus muscle was higher in SNL group significantly (P≤0.05). Discussion & conclusions: The present study demonstrated that decreased activity in the form of SNL is associated with increased NT-4 gene expression in soleus muscle. However, the mechanisms and pathophysiologic issues of this increase are remaining elusive.

Growth hormone protects against kainate excitotoxicity and induces BDNF and NT3 expression in chicken neuroretinal cells

There is increasing evidence to suggest a beneficial neuroprotective effect of growth hormone (GH) in the nervous system. While our previous studies have largely focused on retinal ganglion cells (RGCs), we have also found conclusive evidence of a pro-survival effect of GH in cells of the inner nuclear layer (INL) as well as a protective effect on the dendritic trees of the inner plexiform layer (IPL) in the retina. The administration of GH in primary neuroretinal cell cultures protected and induced neural outgrowths. Our results, both in vitro (embryo) and in vivo (postnatal), showed neuroprotective actions of GH against kainic acid (KA)-induced excitotoxicity in the chicken neuroretina. Intravitreal injections of GH restored brain derived neurotrophic factor (BDNF) expression in retinas treated with KA. In addition, we demonstrated that GH over-expression and exogenous administration increased BDNF and neurotrophin-3 (NT3) gene expression in embryonic neuroretinal cells. Thus, GH neuroprotective actions in neural tissues may be mediated by a complex cascade of neurotrophins and growth factors which have been classically related to damage prevention and neuroretinal tissue repair.

Selective decline of neurotrophin and neurotrophin receptor genes within CA1 pyramidal neurons and hippocampus proper: Correlation with cognitive performance and neuropathology in mild cognitive impairment and Alzheimer's disease.

Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction during the progression of AD.

Knockout of toll-like receptor impairs nerve regeneration after a crush injury

BackgroundToll-like receptors (TLRs) are involved in the initiation of Schwann cell activation and subsequent recruitment of macrophages for clearance of degenerated myelin and neuronal debris after nerve injury. The present study was designed to investigate the regenerative outcome and expression of myelination-related factors in Tlr-knockout mice following a sciatic nerve crush injury.Materials and methodsA standard sciatic nerve crush injury, induced by applying constant pressure to the nerve with a No. 5 jeweler's forceps for 30 s, was performed in C57BL/6, Tlr2−/−, Tlr3−/−, Tlr4−/−, Tlr5−/−, and Tlr7−/− mice. Quantitative histomorphometric analysis of toluidine blue-stained nerve specimens and walking track analysis were performed to evaluate nerve regeneration outcomes. PCR Arrays were used to detect the expression of neurogenesis-related genes of dorsal root ganglia as well as of myelination-related genes of the distal nerve segments.ResultsWorse nerve regeneration after nerve crush injury was found in all Tlr-knockout mice than in C57BL/6 mice. Delayed expression of myelin genes and a different expression pattern of myelination-related neurotrophin genes and transcription factors were found in Tlr-knockout mice in comparison to C57BL/6 mice. In these TLR-mediated pathways, insulin-like growth factor 2 and brain-derived neurotrophic factor, as well as early growth response 2 and N-myc downstream-regulated gene 1, were significantly decreased in the early and late stages, respectively, of nerve regeneration after a crush injury.ConclusionsKnockout of Tlr genes decreases the expression of myelination-related factors and impairs nerve regeneration after a sciatic nerve crush injury.

Progress in the role of neurotrophin-3 and its receptors in the development of cochlear spiral ganglion in rats

Neurotrophin-3 (NT-3) attracted increasing attention about NTFs researches in recent years. But the mechanism of promoting the development of neurons and neurite extension is not clear. Recombinant human NT-3 or NT-3 gene is commonly used in the treatment of peripheral and central neurons system damage. When rats are born, the cochlear is not mature yet. It is a suitable experimental animal for studying the morphological and functional development of the peripheral auditory pathway. It was found that NT-3 could promote the survival, growth, division and extension of the cochlear neurons in rats. To make clear the role of NT-3 in the development of spiral ganglion in the rat cochlear will be of significance for the treatment of nervous hearing loss by NT-3 in the future.

In vitro non-viral murine pro-neurotrophin 3 gene transfer into rat bone marrow stromal cells

Neurotrophin 3 (NT-3) is an important factor for promoting prenatal neural development, as well as regeneration, axogenesis and plasticity in postnatal life. Therapy with NT-3 was reported to improve the condition of patients suffering from degenerative diseases and traumatic injuries, however, the disadvantage of NT-3 protein delivery is its short half-life, thus our alternative approach is the use of NT-3 gene therapy. In this study, the bone marrow stromal cells (BMSCs) were isolated from adult rats, cultured for 4 passages and transfected with either pEGFP-N1 or a constructed vector containing murine proNT-3 (pSecTag2/HygroB-murine proNT-3) using Lipofectamine 2000 followed by Hygromycin B (200mg/kg). The transfection efficiency of the transiently transfected BMSCs was evaluated using the green fluorescence protein containing vector (pEGFP-N1). A quantitative evaluation of the NT-3 expression of mRNA using real time qRT-PCR shows that there was double fold increase in NT-3 gene expression compared with non-transfected BMSCs, also, the culture supernatant yielded double fold increase in NT-3 using ELISA technique, the data were supported by immunoblotting technique. This suggests that the use of this transfection technique can be useful for gene therapy in different neurological disorders with neurodegenerative or traumatic origins.

Optical coherence tomography and T cell gene expression analysis in patients with benign multiple sclerosis.

Benign multiple sclerosis is a retrospective diagnosis based primarily on a lack of motor symptom progression. Recent findings that suggest patients with benign multiple sclerosis experience non-motor symptoms highlight the need for a more prospective means to diagnose benign multiple sclerosis early in order to help direct patient care. In this study, we present optical coherence tomography and T cell neurotrophin gene analysis findings in a small number of patients with benign multiple sclerosis. Our results demonstrated that retinal nerve fiber layer was mildly thinned, and T cells had a distinct gene expression profile that included upregulation of interleukin 10 and leukemia inhibitory factor, downregulation of interleukin 6 and neurotensin high affinity receptor 1 (a novel neurotrophin receptor). These findings add evidence for further investigation into optical coherence tomography and mRNA profiling in larger cohorts as a potential means to diagnose benign multiple sclerosis in a more prospective manner.

Activation of neurotrophins in lumbar dorsal root probably contributes to neuropathic pain after spinal nerve ligation.

Objective(s):Neurotrophins (NTs) exert various effects on neuronal system. Growing evidence indicates that NTs are involved in the pathophysiology of neuropathic pain. However, the exact role of these proteins in modulating nociceptive signaling requires being defined. Thus, the aim of this study was to evaluate the effects of spinal nerve ligation (SNL) on NTs activation in the lumbar dorsal root.Materials and Methods:Ten male Wistar rats were randomly assigned to two groups: tight ligation of the L5 spinal nerve (SNL: n=5) and Sham (n=5). In order to produce neuropathic pain, the L5 spinal nerve was tightly ligated (SNL). Then, allodynia and hyperalgesia tests were conducted weekly. After 4 weeks, tissue samples were taken from the two groups for laboratory evaluations. Here, Real-Time PCR quantity method was used for measuring NTs gene expression levels.Results:SNL resulted in a significant weight loss in the soleus muscle (P<0.05), mechanical allodynia and thermal hyperalgesia thresholds (respectively, P<0.05; P<0.05). Also, NGF, NT-4, NT-3, TrkA, TrkB and TrkC expression were up-regulated following spinal nerve ligation group (respectively, P=0.025, P=0.013, P=0.001, P=0.002, P<0.001, P=001) (respectively, 4.7, 5.2, 7.5, 5.1, 7.2, 6.2 folds).Conclusion:The present study provides new evidence that neuropathic pain induced by spinal nerve ligation probably activates NTs and Trk receptors expression in DRG. However, further studies are needed to better elucidate the role of NTs in a neuropathic pain.

Neurotrophin-3 promotes proliferation and cholinergic neuronal differentiation of bone marrow- derived neural stem cells via notch signaling pathway

AimsRecently, the potential for neural stem cells (NSCs) to be used in the treatment of Alzheimer's disease (AD) has been reported; however, the therapeutic effects are modest by virtue of the low neural differentiation rate. In our study, we transfected bone marrow-derived NSCs (BM-NSCs) with Neurotrophin-3 (NT-3), a superactive neurotrophic factor that promotes neuronal survival, differentiation, and migration of neuronal cells, to investigate the effects of NT-3 gene overexpression on the proliferation and differentiation into cholinergic neuron of BM-NSCs in vitro and its possible molecular mechanism. Main methodsBM-NSCs were generated from BM mesenchymal cells of adult C57BL/6 mice and cultured in vitro. After transfected with NT-3 gene, immunofluorescence and RT-PCR method were used to determine the ability of BM-NSCs on proliferation and differentiation into cholinergic neuron; Acetylcholine Assay Kit was used for acetylcholine (Ach). RT-PCR and WB analysis were used to characterize mRNA and protein level related to the Notch signaling pathway. Key findingsWe found that NT-3 can promote the proliferation and differentiation of BM-NSCs into cholinergic neurons and elevate the levels of acetylcholine (ACh) in the supernatant. Furthermore, NT-3 gene overexpression increase the expression of Hes1, decreased the expression of Mash1 and Ngn1 during proliferation of BM-NSCs. Whereas, the expression of Hes1 was down-regulated, and Mash1 and Ngn1 expression were up-regulated during differentiation of BM-NSCs. SignificanceOur findings support the prospect of using NT-3-transduced BM-NSCs in developing therapies for AD due to their equivalent therapeutic potential as subventricular zone-derived NSCs (SVZ-NSCs), greater accessibility, and autogenous attributes.

Cell Transplantation and Neuroengineering Approach for Spinal Cord Injury Treatment: A Summary of Current Laboratory Findings and Review of Literature.

Spinal cord injury (SCI) can cause severe traumatic injury to the central nervous system (CNS). Current therapeutic effects achieved for SCI in clinical medicine show that there is still a long way to go to reach the desired goal of full or significant functional recovery. In basic medical research, however, cell transplantation, gene therapy, application of cytokines, and biomaterial scaffolds have been widely used and investigated as treatments for SCI. All of these strategies when used separately would help rebuild, to some extent, the neural circuits in the lesion area of the spinal cord. In light of this, it is generally accepted that a combined treatment may be a more effective strategy. This review focuses primarily on our recent series of work on transplantation of Schwann cells and adult stem cells, and transplantation of stem cell-derived neural network scaffolds with functional synapses. Arising from this, an artificial neural network (an exogenous neuronal relay) has been designed and fabricated by us-a biomaterial scaffold implanted with Schwann cells modified by the neurotrophin-3 (NT-3) gene and adult stem cells modified with the TrkC (receptor of NT-3) gene. More importantly, experimental evidence suggests that the novel artificial network can integrate with the host tissue and serve as an exogenous neuronal relay for signal transfer and functional improvement of SCI.

Inhibition of long non-coding RNA IGF2AS has profound effect on inducing neuronal growth and protecting local-anesthetic induced neurotoxicity in dorsal root ganglion neurons.

Long non-coding RNA IGF2AS was initially identified as a cancer regulator in wilm's tumors. In this study, IGF2AS was investigated of its functions in inducing neural development and protecting local-anesthetic induced neurotoxicity in dorsal root ganglion (DRG) in spinal cord. Explant of mouse spinal cord DRG was transfected with IGF2AS specific siRNA. The effect of IGF2AS inhibition on neural development was assessed by neurite growth assay, qRT-PCR and western blot assay, respectively. IGF2AS-downregulated DRG explant was then exposed to local anesthetic agent, lidocaine in vitro. The possible protective effects of IGF2AS inhibition on lidocaine-induced DRG neuron apoptosis and neurite loss were further assessed by TUNEL assay, neurite growth assay, qRT-PCR and western blot assays. SiRNA-mediated IGF2AS inhibition promoted neuronal growth, and induced IGF2, BDNF and NT3 upregulations at both gene and protein expressions. In lidocaine-exposed DRG neurons, endogenous IGF2AS inhibition was effective to protect local-anesthetic induced neuronal apoptosis and neurite loss. Further molecular characterization demonstrated that the neuronal protection of IGF2AS inhibition was also associated with upregulations of IGF2, BDNF and NT3 in DRG neurons. Inhibiting endogenous IGF2AS may promote neuronal growth and protect local-anesthetic induced neurotoxicity in DRG neurons, possibly through complimentary IGF2 upregulation and autocrine activation neurotrophin genes.

Side-stream tobacco smoke-induced airway hyperresponsiveness in early postnatal period is involved nerve growth factor

Epidemiological studies have shown that children are more susceptible to adverse respiratory effects of passive smoking than adults. The goal of this study is to elucidate the possible neural mechanism induced by exposure to passive smoking during early life. Postnatal day (PD) 2 and PD 21mice were exposed to side-stream tobacco smoke (SS), a surrogate to secondhand smoke, or filtered air (FA) for 10 consecutive days. Pulmonary function, substance P (SP) airway innervation, neurotrophin gene expression in lung and nerve growth factor (NGF) release in bronchoalveolar lavage (BAL) fluid were measured at different times after the last SS or FA exposure. Exposure to SS significantly altered pulmonary function in PD2, accompanied with an enhanced SP innervation in airway. However, exposure to SS during the later developmental period (PD21) did not appear to affect pulmonary function and SP innervation of the airways. Interestingly, SS exposure in PD2 group significantly induced an increased gene expression on NGF, and decreased NGF receptor P75 in lung; parallel with high levels of NGF protein in BAL. Furthermore, pretreatment with NGF antibody significantly diminished SS-induced airway hyperresponsivenss and the increased SP airway innervation in the PD2 group. These findings suggest that enhanced NGF released in the lung contributes to SS-enhanced SP tracheal innervation and airway responsiveness in early life.

Effects of Neurotrophin-3 Plasmids on Myocyte Apoptosis and Ca2+-ATPase Content in the Muscle After Nerve Injury in Rats

We estimated the influence of plasmids with DNA carrying the neurotrophin-3 (NT-3) gene on apoptosis in the gastrocnemius muscle and content of Ca2+-ATPase in the latter after sciatic nerve injury. Sixty adult Wistar rats were randomly divided into the saline (control) and NT-3 groups. The related indices, such as expression of caspase-3 protein, the rate of apoptosis in the muscle evaluated using a TUNEL technique, and the level of Ca2+-ATPase estimated using Western blot, were observed. Expression of caspase-3 protein was elevated at different post-operative times after peripheral nerve injury; NT-3 expression and the rate of muscle cell apoptosis decreased, whereas the level of Ca2+-ATPase in the sarcoplasmic reticulum increased; significant differences were observed compared with the saline group (P < 0.05). The mitigation mechanism of NT-3 on muscle atrophy after peripheral nerve injury is expressed as inhibition of caspase-3 gene expression, increase in the Ca2+-ATPase level, and reduction in the rate of muscle apoptosis.

Neonatal hyperoxia induces alterations in neurotrophin gene expression

Each year in the United States, nearly 500,000 infants a year are born prematurely. Babies born before 35 weeks gestation are often placed on ventilators and/or given supplemental oxygen. This increase in oxygen, while critical for survival, can cause long-term damage to lungs, retinas and brains. In particular, hyperoxia causes apoptosis in neurons and alters glial activity. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are members of the neurotrophin family of proteins that function to promote the growth, differentiation and development of the nervous system. We hypothesized that hyperoxia can alter the regulation of these genes and by doing so adversely affect the development of the brain. We predicted that mice exposed to hyperoxic conditions would have differences in BDNF and GDNF mRNA expression and relative level of methylated promoter regions coinciding with differences in the relative levels of DNMT1 and DNMT3a mRNA expression. To test this hypothesis, newborn C57Bl/6 mice and their littermates were placed in hyperoxic or normoxic conditions from postnatal day 7 to 12. There were significant decreases in BDNF mRNA expression in the prefrontal cortex following hyperoxia, but a significant increase in the isocortex. GDNF mRNA expression was significantly increased in both the isocortex and prefrontal cortex following hyperoxia. DNMT1 mRNA expression was significantly decreased in the isocortex but significantly increased in the prefrontal following hyperoxia. Together these data suggest that short-term exposure to hyperoxic conditions can affect the regulation and expression of BDNF and GDNF potentially leading to alterations in neural development.

Rare variants in the neurotrophin signaling pathway implicated in schizophrenia risk

Multiple lines of evidence corroborate impaired signaling pathways as relevant to the underpinnings of schizophrenia. There has been an interest in neurotrophins, since they are crucial mediators of neurodevelopment and in synaptic connectivity in the adult brain. Neurotrophins and their receptors demonstrate aberrant expression patterns in cortical areas for schizophrenia cases in comparison to control subjects. There is little known about the contribution of neurotrophin genes in psychiatric disorders. To begin to address this issue, we conducted high-coverage targeted exome capture in a subset of neurotrophin genes in 48 comprehensively characterized cases with schizophrenia-related psychosis. We herein report rare missense polymorphisms and novel missense mutations in neurotrophin receptor signaling pathway genes. Furthermore, we observed that several genes have a higher propensity to harbor missense coding variants than others. Based on this initial analysis we suggest that rare variants and missense mutations in neurotrophin genes might represent genetic contributions involved across psychiatric disorders.

Insertion trauma and recovery of function after cochlear implantation: Evidence from objective functional measures

Partial loss and subsequent recovery of cochlear implant function in the first few weeks following cochlear implant surgery has been observed in previous studies using psychophysical detection thresholds. In the current study, we explored this putative manifestation of insertion trauma using objective functional measures: electrically-evoked compound action potential (ECAP) amplitude-growth functions (ECAP amplitude as a function of stimulus level). In guinea pigs implanted in a hearing ear with good post-implant hearing and good spiral ganglion neuron (SGN) survival, consistent patterns of ECAP functions were observed. The slopes of ECAP growth functions were moderately steep on the day of implant insertion, decreased to low levels over the first few days after implantation and then increased slowly over several weeks to reach a relatively stable level. In parallel, ECAP thresholds increased over time after implantation and then recovered, although more quickly, to a relatively stable low level as did thresholds for eliciting a facial twitch. Similar results were obtained in animals deafened but treated with an adenovirus with a neurotrophin gene insert that resulted in good SGN preservation. In contrast, in animals implanted in deaf ears that had relatively poor SGN survival, ECAP slopes reached low levels within a few days after implantation and remained low. These results are consistent with the idea that steep ECAP growth functions require a healthy population of auditory nerve fibers and that cochlear implant insertion trauma can temporarily impair the function of a healthy SGN population.This article is part of a Special Issue entitled <IEB Kyoto>.

The role of neurotrophins and neurexins genes in the risk of paranoid schizophrenia in Russians and Tatars

Schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development.

BDNF-TrkB Pathway Mediates Neuroprotection of Hydrogen Sulfide against Formaldehyde-Induced Toxicity to PC12 Cells

Formaldehyde (FA) is a common environmental contaminant that has toxic effects on the central nervous system (CNS). Our previous data demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator, has protective effects against FA-induced neurotoxicity. As is known to all, Brain-derived neurotropic factor (BDNF), a member of the neurotrophin gene family, mediates its neuroprotective properties via various intracellular signaling pathways triggered by activating the tyrosine kinase receptor B (TrkB). Intriguingly, our previous data have illustrated the upregulatory role of H2S on BDNF protein expression in the hippocampus of rats. Therefore, in this study, we hypothesized that H2S provides neuroprotection against FA toxicity by regulating BDNF-TrkB pathway. In the present study, we found that NaHS, a donor of H2S, upregulated the level of BDNF protein in PC12 cells, and significantly rescued FA-induced downregulation of BDNF levels. Furthermore, we found that pretreatment of PC12 cells with K252a, an inhibitor of the BDNF receptor TrkB, markedly reversed the inhibition of NaHS on FA-induced cytotoxicity and ablated the protective effects of NaHS on FA-induced oxidative stress, including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA). We also showed that K252a abolished the inhibition of NaHS on FA-induced apoptosis, as well as the activation of caspase-3 in PC12 cells. In addition, K252a reversed the protection of H2S against FA-induced downregulation of Bcl-2 protein expression and upregulation of Bax protein expression in PC12 cells. These data indicate that the BDNF-TrkB pathway mediates the neuroprotection of H2S against FA-induced cytotoxicity, oxidative stress and apoptosis in PC12 cells. These findings provide a novel mechanism underlying the protection of H2S against FA-induced neurotoxicity.