Synthesis Of Neurotrophic Factors Research Articles

Moving to Improve Mental Health - The Role of Exercise in Cognitive Function: A Narrative Review.

This review study investigates how exercise can enhance cognitive ability and mental wellness. Physical activity has been linked to a number of beneficial effects on cognitive function, including increased memory and executive function in adults, improved academic performance in children and adolescents, and potential advantages for people with cognitive impairments or neurodegenerative diseases. Increased cerebral blood flow, the synthesis of neurotrophic factors, and a decrease in oxidative stress and inflammation are the processes driving these effects. Studies have shown that exercise has mood-regulating benefits, with symptoms of anxiety and sadness lessening as a result. These mood-enhancing effects are a result of the endocannabinoid system being activated, endorphins being released, and changes in self-esteem and body image. Exercise therapies have also demonstrated the potential to encourage cognitive health as people age and lower the likelihood of cognitive decline. Exercise has been investigated as an adjuvant treatment for mental health illnesses, such as depression, anxiety disorders, schizophrenia, bipolar disorder, and eating disorders, in addition to its preventive effects. Exercise can improve the effectiveness of treatment and general wellbeing when it is incorporated into comprehensive treatment strategies. To identify the ideal exercise parameters for certain outcomes and overcome barriers to exercise participation, more study is necessary. We can get closer to enhancing general wellbeing and quality of life by including exercise in measures for promoting mental health and cognitive health.

Influence of neurotrophic factors on protein composition during somatic nerve injury and regeneration

The quantity of neurotrophic factors and the protein composition of somatic nerve membranes in rats during injury and survival of nerves under the action of clobetasol have been explored. It has been shown that the drug administered intramuscularly produces more pronounced effect on the increase in the level of neurotrophic growth factors and structural proteins responsible for recovery processes than the drug released from hydrogel derived from microbial polysaccharides as well as stabilizes the content of the total protein fraction of damaged somatic nerves. Proteins of the injured neural conductor are less degraded during intramuscular injection of clobetasol probably because of better availability of the drug administered by injection than availability of the drug administered (slow drug release) from hydrogel composite. In addition, an increase in the amount of DNA and some protein fractions indicates that clobetasol is able to participate in an activation of genes associated with remyelination. We suppose that clobetasol can stimulate synthesis of neurotrophic growth factors, thereby triggering phosphatidylinositol-3-kinase and mitogen-activated protein kinase signaling pathways that regulate the processes of cytoskeletal reorganization and axonal growth, as well as enhance the rate of synthesis of structural and axonal proteins necessary to restore the functional activity of injured nerve conductors.

Huntington-associated protein 1 inhibition contributes to neuropathic pain by suppressing Cav1.2 activity and attenuating inflammation.

Although pain dysfunction is increasingly observed in Huntington disease, the underlying mechanisms still unknown. As a crucial Huntington-associated protein, Huntington-associated protein 1 (HAP1) is enriched in normal spinal dorsal horn and dorsal root ganglia (DRG) which are regarded as "primary sensory center," indicating its potential functions in pain process. Here, we discovered that HAP1 level was greatly increased in the dorsal horn and DRG under acute and chronic pain conditions. Lack of HAP1 obviously suppressed mechanical allodynia and hyperalgesia in spared nerve injury (SNI)-induced and chronic constriction injury-induced pain. Its deficiency also greatly inhibited the excitability of nociceptive neurons. Interestingly, we found that suppressing HAP1 level diminished the membrane expression of the L-type calcium channel (Cav1.2), which can regulate Ca 2+ influx and then influence brain-derived neurotrophic factor (BDNF) synthesis and release. Furthermore, SNI-induced activation of astrocytes and microglia notably decreased in HAP1-deficient mice. These results indicate that HAP1 deficiency might attenuate pain responses. Collectively, our results suggest that HAP1 in dorsal horn and DRG neurons regulates Cav1.2 surface expression, which in turn reduces neuronal excitability, BDNF secretion, and inflammatory responses and ultimately influences neuropathic pain progression.

Role of Probiotics and Diet in the Management of Neurological Diseases and Mood States: A Review.

Alzheimer's (AD) and Parkinson's diseases (PD) are common in older people. Autism spectrum disorders (ASD), anxiety, depression, stress, and cognitive impairment are prevalent among people irrespective of age. The incidence of neurological disorders has been increasing in recent decades. Communication between the gut microbiota and the brain is intrinsically complicated, and it is necessary for the maintenance of the gut, brain, and immune functions of the host. The bidirectional link among the gut, gut microbiota and the brain is designated as the "microbiota-gut-brain axis." Gut microbiota modulates the host immune system and functions of tissue barriers such as gut mucosa and blood-brain barrier (BBB). Gut microbial dysfunction disturbs the gut-brain interplay and may contribute to various gut disorders, neurocognitive and psychiatric disorders. Probiotics could protect intestinal integrity, enhance gut functions, promote intestinal mucosal and BBB functions, and support the synthesis of brain-derived neurotrophic factors, which enhance neuronal survival and differentiation. Probiotics could be considered an adjunct therapy to manage metabolic and psychiatric diseases. Predominantly, Lactobacillus and Bifidobacterium strains are documented as potent probiotics, which help to maintain the bidirectional interactions between the gut and brain. The consumption of probiotics and probiotics containing fermented foods could improve the gut microbiota. The diet impacts gut microbiota, and a balanced diet could maintain the integrity of gut-brain communication by facilitating the production of neurotrophic factors and other neuropeptides. However, the beneficial effects of probiotics and diet might depend upon several factors, including strain, dosage, duration, age, host physiology, etc. This review summarizes the importance and involvement of probiotics and diet in neuroprotection and managing representative neurological disorders, injuries and mood states.

Progress of researches on involvement of corticospinal tract in the effect of acupuncture on improvement of post-stroke motor dysfunction

The corticospinal tract (CST), descending from the frontoparietal cortex and traveling down to terminate at the anterior horn of the spinal cord to mediate voluntary movements, is frequently injured from the infarcted or hemorrhagic cerebrovascular insults due to stroke. Under the circumstances, motor dysfunction seriously affects the patient's quality of life. Acupuncture therapy has a sequelae, especially in improving motor deficits. In the present paper, we reviewed the current development of researches on acupuncture treatment of poststroke motor dysfunction and its biological mechanisms from 1) delaying patients' development of neuronal degeneration and white matter fibrosis (Wallerian degeneration), 2) improving patients' upper limb motor function and daily life ability by promoting the repair of white matter tracts and CST on the affected side, 3) promoting the compensation of CST on the healthy side, 4) reconstructing the motor conduction pathway to strengthen the bilateral brain connection in ex-perimental animals, and 5) strengthening the sprouting of the contralateral CST to dominate the affected side again across the midline. In addition, acupuncture stimulation induced improvement of axonal rewiring for corticospinal innervation is also possibly related to its functions in accelerating the synthesis and release of neurotrophic factors, down-regulating Nogo-A/RhoA signaling and activating vascular epithelial growth factor/Dll4/Notch signaling pathways.

Nitric Oxide Linked to mGluR5 Upregulates BDNF Synthesis by Activating MMP2 in the Caudate and Putamen after Challenge Exposure to Nicotine in Rats.

Nitric oxide (NO) linked to glutamate receptors in the caudate and putamen (CPu) regulates neuroadaptation after drug exposure. Matrix-metalloproteinase (MMP), a Ca2+-dependent zinc-containing endopeptidase, increases mature brain-derived neurotrophic factor (BDNF) synthesis after drug exposure in the brain. The present study determined that NO synthesis linked to metabotropic glutamate receptor subtype 5 (mGluR5) stimulation after challenge exposure to nicotine activates MMP, which upregulates BDNF synthesis in the CPu. Subcutaneous injection of challenge nicotine (1.0 mg/kg) after repeated injections of nicotine (1.0 mg/kg/day) for 14 days and 7 days of nicotine withdrawal increased MMP2 activity and BDNF expression in the CPu of rats. These increases were prevented by the bilateral intra-CPu infusion of the mGluR5 antagonist, MPEP (0.1 nmol/side), the IP3 receptor antagonist, xestospongin C (0.004 nmol/side) or the neuronal nitric oxide synthase (nNOS) and NO inhibitor, Nω-propyl (0.1 nmol/side) prior to the challenge nicotine. Furthermore, bilateral intra-CPu infusion of the MMP2 inhibitor, OA-Hy (1 nmol/side) prevented the challenge nicotine-induced increase in the expression of BDNF. These findings suggest that elevation of NO synthesis linked to mGluR5 potentiates BDNF synthesis via activation of MMP2 after challenge exposure to nicotine in the CPu of rats.

The neuroprotective effects of glucagon-like peptide 1 in Alzheimer's and Parkinson's disease: An in-depth review.

Currently, there is no disease-modifying treatment available for Alzheimer’s and Parkinson’s disease (AD and PD) and that includes the highly controversial approval of the Aβ-targeting antibody aducanumab for the treatment of AD. Hence, there is still an unmet need for a neuroprotective drug treatment in both AD and PD. Type 2 diabetes is a risk factor for both AD and PD. Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor that has shown neuroprotective effects in preclinical studies, and the success of GLP-1 mimetics in phase II clinical trials in AD and PD has raised new hope. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. GLP-1 analogs are safe, well tolerated, resistant to desensitization and well characterized in the clinic. Herein, we review the existing evidence and illustrate the neuroprotective pathways that are induced following GLP-1R activation in neurons, microglia and astrocytes. The latter include synaptic protection, improvements in cognition, learning and motor function, amyloid pathology-ameliorating properties (Aβ, Tau, and α-synuclein), the suppression of Ca2+ deregulation and ER stress, potent anti-inflammatory effects, the blockage of oxidative stress, mitochondrial dysfunction and apoptosis pathways, enhancements in the neuronal insulin sensitivity and energy metabolism, functional improvements in autophagy and mitophagy, elevated BDNF and glial cell line-derived neurotrophic factor (GDNF) synthesis as well as neurogenesis. The many beneficial features of GLP-1R and GLP-1/GIPR dual agonists encourage the development of novel drug treatments for AD and PD.

Transgenerational Abnormalities Induced by Paternal Preconceptual Alcohol Drinking: Findings from Humans and Animal Models.

Alcohol consumption during pregnancy and lactation is a widespread preventable cause of neurodevelopmental impairment in newborns. While the harmful effects of gestational alcohol use have been well documented, only recently, the role of paternal preconceptual alcohol consumption (PPAC) prior to copulating has drawn specific epigenetic considerations. Data from human and animal models have demonstrated that PPAC may affect sperm function, eliciting oxidative stress. In newborns, PPAC may induce changes in behavior, cognitive functions, and emotional responses. Furthermore, PPAC may elicit neurobiological disruptions, visuospatial impairments, hyperactivity disorders, motor skill disruptions, hearing loss, endocrine, and immune alterations, reduced physical growth, placental disruptions, and metabolic alterations. Neurobiological studies on PPAC have also disclosed changes in brain function and structure by disrupting the growth factors pathways. In particular, as shown in animal model studies, PPAC alters brain nerve growth factor (NGF) and brainderived neurotrophic factor (BDNF) synthesis and release. This review shows that the crucial topic of lifelong disabilities induced by PPAC and/or gestational alcohol drinking is quite challenging at the individual, societal, and familial levels. Since a nontoxic drinking behavior before pregnancy (for both men and women), during pregnancy, and lactation cannot be established, the only suggestion for couples planning pregnancies is to completely avoid the consumption of alcoholic beverages.

EFFECT OF GLYPROLINES ON THE LEVEL OF APOPTOTIC AND NEUROTROPHIC FACTORS UNDER CONDITIONS OF “SOCIAL” STRESS

The aim of the article was to study the effect of glyproline neuropeptide compounds Thr–Lys–Pro–Arg–Pro–Gly–Pro (Selank), Pro–Gly–Pro and Pro–Gly–Pro–Leu, on the level of apoptotic factors (caspase-3, caspase-8, the tumor necrosis factor) and neurotrophic factors (the nerve growth factor and the brain neurotrophic factor) in the blood serum of white rats under the experimental modeling of “social” stress.Materials and methods. The experimental studies were carried out on 90 nonlinear white male rats aged 6 months. By the type of behavior, in the process of “social” stress modeling, all the rats were divided into “aggressors” and “victims”. In the study, the following experimental groups (n=10) were formed: control individuals; groups of the rats exposed to stress for 20 days; groups of the animals treated intraperitoneally at the dose of 100 μg/kg/day, starting from the 1st day of the stress factor exposure, with a course of 20 days of glyproline compounds Thr–Lys–Pro–Arg–Pro–Gly–Pro (Selank), Pro–Gly–Pro and Pro–Gly–Pro–Leu. The effect of the compounds on the level of apoptotic and neurotrophic factors was assessed by determining the level of caspase-3, caspase-8, the tumor necrosis factor, the nerve growth factor and the brain neurotrophic factor of white rat blood serum by enzyme immunoassay.Results. According to the results of the study, it was found out that under the conditions of “social” stress, there was an increase in the apoptotic processes accompanied by an increase in the level of caspase-3, caspase-8, TNF-α in the blood serum of white rats, as well as a decrease in the concentration of neurotrophic factors – BDNF and NGF. The administration of giproline compounds against the background of stress, contributed to the restoration of the studied indicators level, which is most likely due to the presence of antiapoptotic and neuroprotective effects in giprolines due to the inhibition of the caspase-dependent cascade of apoptosis reactions, as well as the induction of the synthesis of neurotrophic factors with the antiapoptotic activity.Conclusion. Thus, the administration of glyproline neuropeptide compounds Thr–Lys–Pro–Arg–Pro–Gly–Pro (Selank), Pro–Gly–Pro and Pro–Gly–Pro–Leu under stress conditions, contributes to the restoration of the initiating and effector caspases level, as well as of neurotrophic factors. As a result of the experiment, an anti-apoptotic effect is observed due to the inhibition of the caspase-dependent cascade of reactions, as well as a stress-protective effect is observed due to the restoration of the brain neurotrophic factors level.

Apelin-13 activates the hippocampal BDNF/TrkB signaling pathway and suppresses neuroinflammation in male rats with cisplatin-induced cognitive dysfunction

It has been established that cisplatin causes neuronal damage and cognitive impairment. However, the mechanism is not sufficiently clear. Apelin-13 is an endogenous peptide with strong neuroprotective effects through the synthesis of neurotrophic factors and suppression of inflammation. The aim of this study was to investigate the role of brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling pathway and the potential inhibitory effects of apelin-13 in the mechanism of cisplatin-induced hippocampal damage and cognitive impairment. Apelin-13 was administered to adult sprague dawley male rats at a dose of 20 nmol/kg every day for 4 weeks, cisplatin was administered at a dose of 5 mg/kg once a week for 4 weeks. The spatial and recognition memory tests of the rats were performed on the 5th week. BDNF and the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels were measured by ELISA in hippocampal homogenates. Pyramidal neuron and glial cell damage in the hippocampal CA1, CA3 and dentate gyrus (DG) were analyzed histologically. TrkB activity in the hippocampus was determined by immunohistochemical methods. Cisplatin impaired spatial and recognition memory in rats, while apelin-13 improved spatial memory but did not affect recognition memory. Cisplatin suppressed BDNF in the hippocampus while increased IL-1β and TNF-α. In contrast, apelin-13 administration increased BDNF but significantly suppressed TNF-α and IL-1B. Cisplatin caused pyramidal neuron and glial cell damage in CA1, CA3 and DG. In the cisplatin + apelin-13 group, however, pyramidal neuron and glial cell damage was less than those without apelin-13. Cisplatin increased TrkB activity in the hippocampus, which was counteracted by apelin-13. In conclusion, apelin-13 reduced the cisplatin-induced cognitive deficiency, by suppressing inflammation and stimulating the synthesis and activation of neurotrophic factors in hippocampal tissue.

Heterogeneity of the mechanisms of action of antidepressants

The article discusses the heterogeneous mechanisms of the pharmacodynamics of antidepressants that underlie the therapeutic response. Sharing the similar clinical activity, antidepressants determine the development of drug-induced homeostasis by means of different molecular mechanisms (selective or nonselective blockade of monoamine reuptake, inhibition of monoamine oxidase, blockade of certain monoamine receptors). However, an increase of serotonin and other monoamines concentrations in the synapses of the central nervous system is only the initiating factor in the development of specific clinical effects. The latter are probably determined by other neurochemical effects, including changes in the density of postsynaptic receptors and an increase in the synthesis of neurotrophic factors. However, the primary mechanisms that increase monoamine concentrations in the synapses might not always “work properly”, leading to the lack of efficacy of the initial antidepressant, while the probability of the therapeutic response to the subsequent antidepressant remains rather high. Thus, the efficacy of an antidepressant may depend on the baseline differences in the neurochemical state contributing to the pathological “depressive” homeostasis. The heterogeneous neurochemical effects of antidepressants can determine the dissociation of existing neuronal interactions, leading to the development of the new — druginduced — homeostasis. At the same time, it is possible that stimulation of general neurotrophic processes by antidepressants may contribute to the progression and chronicity of pathology due to the ambiguous influence on certain stages of the pathological process. This determines the significance of neurophysiological studies of central disturbances in depression and search of fundamentally new neurochemical targets for the treatment of depressive states associated with various mental disorders.

Molecular targets for endogenous glial cell line-derived neurotrophic factor modulation in striatal parvalbumin interneurons

Administration of recombinant glial cell line-derived neurotrophic factor into the putamen has been tested in preclinical and clinical studies to evaluate its neuroprotective effects on the progressive dopaminergic neuronal degeneration that characterizes Parkinson’s disease. However, intracerebral glial cell line-derived neurotrophic factor infusion is a challenging therapeutic strategy, with numerous potential technical and medical limitations. Most of these limitations could be avoided if the production of endogenous glial cell line-derived neurotrophic factor could be increased. Glial cell line-derived neurotrophic factor is naturally produced in the striatum from where it exerts a trophic action on the nigrostriatal dopaminergic pathway. Most of striatal glial cell line-derived neurotrophic factor is synthesized by a subset of GABAergic interneurons characterized by the expression of parvalbumin. We sought to identify molecular targets specific to those neurons and which are putatively associated with glial cell line-derived neurotrophic factor synthesis. To this end, the transcriptomic differences between glial cell line-derived neurotrophic factor-positive parvalbumin neurons in the striatum and parvalbumin neurons located in the nearby cortex, which do not express glial cell line-derived neurotrophic factor, were analysed. Using mouse reporter models, we have defined the genomic signature of striatal parvalbumin interneurons obtained by fluorescence-activated cell sorting followed by microarray comparison. Short-listed genes were validated by additional histological and molecular analyses. These genes code for membrane receptors (Kit, Gpr83, Tacr1, Tacr3, Mc3r), cytosolic proteins (Pde3a, Crabp1, Rarres2, Moxd1) and a transcription factor (Lhx8). We also found the proto-oncogene cKit to be highly specific of parvalbumin interneurons in the non-human primate striatum, thus highlighting a conserved expression between species and suggesting that specific genes identified in mouse parvalbumin neurons could be putative targets in the human brain. Pharmacological stimulation of four G-protein-coupled receptors enriched in the striatal parvalbumin interneurons inhibited Gdnf expression presumably by decreasing cyclic adenosine monophosphate formation. Additional experiments with pharmacological modulators of adenylyl cyclase and protein kinase A indicated that this pathway is a relevant intracellular route to induce Gdnf gene activation. This preclinical study is an important step in the ongoing development of a specific pro-endo-glial cell line-derived neurotrophic factor pharmacological strategy to treat Parkinson’s disease.

Neuropathic Pain Causes a Decrease in the Dendritic Tree Complexity of Hippocampal CA3 Pyramidal Neurons

The International Pain Association defines neuropathic pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” Recent studies show that chronic neuropathic pain causes both morphological and functional changes within brain structures. Due to the impact of supraspinal centers on pain signal processing, patients with chronic pain often suffer from depression, anxiety, memory impairment, and learning disabilities. Changes in hippocampal neuronal and glial plasticity can play a substantial role in the development of these symptoms. Given the special role of the CA3 hippocampal area in chronic stress reactions, we suggested that this region may undergo significant morphological changes as a result of persistent pain. Since the CA3 area is involved in the implementation of hippocampus-dependent memory, changes in the neuronal morphology can cause cognitive impairment observed in chronic neuropathic pain. This study aimed to elucidate the structural and plastic changes within the hippocampus associated with dendritic tree atrophy of CA3 pyramidal neurons in mice with chronic sciatic nerve constriction. Behavioral testing revealed impaired working and long-term memory in mice with a chronic constriction injury. Using the Golgi-Cox method, we revealed a decrease in the number of branches and dendritic length of CA3 pyramidal neurons. The dendritic spine number was decreased, predominantly due to a reduction in mushroom spines. An ­immunohistochemical study showed changes in astro- and microglial activity, which could affect the morphology of neurons both directly and indirectly via the regulation of neurotrophic factor synthesis. Using ELISA, we found a decrease in brain-derived neurotrophic factor production and an increase in neurotrophin-3 production. Morphological and biochemical changes in the CA3 area are accompanied by impaired working and long-term memory of animals. Thus, we can conclude that morphological and biochemical changes within the CA3 hippocampal area may underlie the cognitive impairment in neuropathic pain.

Potential Antidepressant Effects of Scutellaria baicalensis, Hericium erinaceus and Rhodiola rosea.

Recent studies focused on the pharmacology and feasibility of herbal compounds as a potential strategy to target a variety of human diseases ranging from metabolic to brain disorders. Accordingly, bioactive ingredients which are found within a variety of herbal compounds are reported to produce both neuroprotective and psychotropic activities which may help to combat mental disorders such as depression, anxiety, sleep disturbances and cognitive alterations. In the present manuscript, we focus on three herbs which appear effective in mitigating anxiety or depression with favourable risk-benefit profiles, namely Scutellaria baicalensis (S. baicalensis), Hericium erinaceus (H. erinaceus) and Rhodiola rosea (R. rosea). These three traditional folk medicinal herbs target the main biochemical events that are implicated in mental disorders, mimicking, to some extent, the mechanisms of action of conventional antidepressants and mood stabilizers with a wide margin of tolerability. In detail, they rescue alterations in neurotransmitter and neuro-endocrine systems, stimulate neurogenesis and the synthesis of neurotrophic factors, and they counteract oxidative stress, mitochondrial dysfunction and inflammation. Albeit the encouraging results that emerge from both experimental and clinical evidence, further studies are needed to confirm and better understand the mental-health promoting, and specifically, the antidepressant effects of these herbs.

Role of Astrocytic Dysfunction in the Pathogenesis of Parkinson's Disease Animal Models from a Molecular Signaling Perspective.

Despite the fact that astrocytes are the most abundant glial cells, critical for brain function, few studies have dealt with their possible role in neurodegenerative diseases like Parkinson's disease (PD). This article explores relevant evidence on the involvement of astrocytes in experimental PD neurodegeneration from a molecular signaling perspective. For a long time, astrocytic proliferation was merely considered a byproduct of neuroinflammation, but by the time being, it is clear that astrocytic dysfunction plays a far more important role in PD pathophysiology. Indeed, ongoing experimental evidence suggests the importance of astrocytes and dopaminergic neurons' cross-linking signaling pathways. The Wnt-1 (wingless-type MMTV integration site family, member 1) pathway regulates several processes including neuron survival, synapse plasticity, and neurogenesis. In PD animal models, Frizzled (Fzd) neuronal receptors' activation by the Wnt-1 normally released by astrocytes following injuries leads to β-catenin-dependent gene expression, favoring neuron survival and viability. The transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor also participates in experimental PD genesis. Activation of astrocyte TRPV1 receptors by noxious stimuli results in reduced inflammatory response and increased ciliary neurotrophic factor (CNTF) synthesis, which enhances neuronal survival and differentiation. Another major pathway involves IκB kinase (IKK) downregulation by ARL6ip5 (ADP-ribosylation-like factor 6 interacting protein 5, encoded by the cell differentiation-associated, JWA, gene). Typically, IKK releases the proinflammatory NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) molecule from its inhibitor. Therefore, by downregulating NF-κB inhibitor, ARL6ip5 promotes an anti-inflammatory response. The evidence provided by neurotoxin-induced PD animal models guarantees further research on the neuroprotective potential of normalizing astrocyte function in PD.

Inhibition of ADAMTS-4 Expression in Olfactory Ensheathing Cells Enhances Recovery after Transplantation within Spinal Cord Injury.

Spinal cord injury (SCI) induces permanent loss of sensitive and motor functions below the injury level. To date, a wide variety of cells has been used as biotherapies to cure SCI in different animal paradigms. Specifically, olfactory ensheathing cells (OECs) is one of the most promising. Indeed, OECs have been shown to enhance recovery in many animal studies. Moreover, OECs transplantation has been applied to a paraplegic patient and have shown beneficial effects. However, it has been reported that the significant level of recovery varies among different patients. Therefore, it is of primary importance to enhance the regenerative efficiency of OECs for better translations. Recently, it has been shown that inhibiting ADAMTS4 expression in glial cells in vitro increases their synthesis of neurotrophic factors. We hypothesized that the expression of neurotrophic factors secreted by OECs can be increased by the deletion of ADAMTS4. Taking advantage of ADAMTS4-/- mouse line, we produce ADAMTS4 deficient primary OEC cultures and then we investigated their regenerative potential after SCI. By using quantitative polymerase chain reaction, bioluminescence imaging, measurement of locomotor activity, electrophysiological studies, and immunohistochemistry, our results show that ADAMTS4-/- olfactory bulb OEC (bOECs) primary cultures upregulate their trophic factor expression in vitro, and that the transplantation of ADAMTS4-/- bOECs in a severe SCI model increases functional recovery and tissue repair in vivo. Altogether, our study reveals, for the first time, that primary bOEC cultures transplantation can be potentialized by inhibition of the expression of ADAMTS4.

SU21 - INTEGRATED ANALYSIS OF MICROARRAY AND PROTEOMICS DATA BY HIPPOCAMPAL RAT NEURONS AND HUMAN IPS NEURONS TREATED WITH DIFFERENT DOSES OF LITHIUM

Background Lithium salts have a well-established role in the treatment of psychiatric disorders as major affective disorders and more recently Alzheimer disease. Experimental and clinical studies have provided evidence that lithium may exert neuroprotective effects at therapeutically and sub therapeutically doses. In animal model and cell culture models, lithium has been shown to increase neuronal viability through a combination of mechanisms that includes the inhibition of apoptosis, regulation of autophagy, increased mitochondrial function, and synthesis of neurotrophic factors. Objective: The Objective of the study is to compare biological process and pathways enriched in hippocampal neurons treated with different doses of lithium (0.02 mM, 0.2 mM and 2 mM) integrating genes and proteins differentially expressed. Methods Primary cultures of hippocampal neurons; Assessment of cell viability; Experimental design considerations, Microarray; LC-MS analyses; Data Analysis; Neural stem cell differentiation in Random differentiation; String Database and Functional enrichment analysis. Results The results showed that growing gene networks using differentially expressed genes and proteins as seeds alterations in mitochondria, ribosome and proteasome were observed in all lithium treatment doses. But also more specific biological process such as mitochondria respiratory chain, energy production (glucose and ATP) and apoptosis biological functions were enriched in each dose treatment. Discussion Given all the analyzes we can see that there is a dissociation dose effect of the treatment with lithium, the dose of 0.02Mm modified genes of degradation pathway proteins. The dose of 0.2Mm altered pathways of energy metabolism and the dose of 2Mm change related to nuclear and nuclear membrane. we can understand the specific function of each dose of the treatment.

Spatial object recognition memory formation under acute stress.

Stress is known to have a critical impact on memory processes. In the present work, we focus on the effects of an acute stress event closely associated to an unrelated learning task. Here, we show that acute stress (elevated platform [EP] session) experienced 1 hr after a weak spatial object recognition (SOR) training, which only induces a short-term memory (STM), promoted the formation of SOR-long term memory (SOR-LTM) in rats. The effect induced by stress was dependent on the activation of glucocorticoid- and mineralocorticoid-receptors, brain-derived neurotrophic factor (BDNF) and protein synthesis in the dorsal hippocampus. In contrast, EP after a strong SOR impaired SOR-LTM probably by interfering with the use of necessary resources. Moreover, we show that the EP session before training induced anterograde interference, which it was not reversed by a subsequent exposure to an open field. Our findings provide novel insights into the impact of stress on LTM formation in rodents and they are discussed under the behavioral analogue of the synaptic tagging and capture hypothesis.

Changes in Retinal Glial Cells with Age and during Development of Age-Related Macular Degeneration.

Age is the major risk factor in the age-related macular degeneration (AMD) which is a complex multifactor neurodegenerative disease of the retina and the main cause of irreversible vision loss in people over 60 years old. The major role in AMD pathogenesis belongs to structure-functional changes in the retinal pigment epithelium cells, while the onset and progression of AMD are commonly believed to be caused by the immune system dysfunctions. The role of retinal glial cells (Muller cells, astrocytes, and microglia) in AMD pathogenesis is studied much less. These cells maintain neurons and retinal vessels through the synthesis of neurotrophic and angiogenic factors, as well as perform supporting, separating, trophic, secretory, and immune functions. It is known that retinal glia experiences morphological and functional changes with age. Age-related impairments in the functional activity of glial cells are closely related to the changes in the expression of trophic factors that affect the status of all cell types in the retina. In this review, we summarized available literature data on the role of retinal macro- and microglia and on the contribution of these cells to AMD pathogenesis.

THE EFFECTS OF ALPHA SYNUCLEIN OVEREXPRESSION ON NEUROTROPHIC FACTORS AND THEIR RECEPTORS IN HUMAN PRIMARY ASTROCYTE CULTURE

Astrocytes are support cells in central nervous system (1). Together with the other neuroglial cells, these cells produce neurotransmitters, hormones, trophic and immune factors and participate in synaptic functions in various stages of development (2). α-synucleinopathies are a group of neurodegenerative disorders which are characterized with abnormal accumulation of α-synuclein protein in the cytoplasm of neurons and glia cells (3). α-synuclein has a role in dopamine release, memory formation and cognitive functions. α-synuclein may also affect the synaptic activity by acting as a chaperone and may be needed in neurotransmitter release in presynaptic nerve terminals (4). Impairment of calcium homeostasis and alterations in synthesis and utilization of neurotrophic factors take part in the most significant common pathological mechanisms of neurodegenerative disorders which also includes α-synucleinopathies (5). Present study was designed in order to determine the general profile of human astrocytes in terms of neurotrophic factor synthesis and secretion, and how this profile is altered in response to α-synuclein overexpression. In the study, the primary human astrocytes was cultured. Human SNCA gene carrying plasmid was transferred to the cells by using a lipid-based transfection agent. Levels of more than 40 intracellular and released trophic factors or their receptors in untreated and α-synuclein overexpressing astrocytes were detected with chemiluminescence-based western/dot blot method by using human growth factor antibody array. Our preliminary results shows that some of the factors from VEGF, PDGF, FGF, EGF class, TGF-β3 from TGF class and NT-4 from neurotrophin class predominately produced, while bNGF is produced low and FGF-4 has nearly no expression in untreated astrocytes. α-synuclein overexpression in astrocytes highly altered the profile described above. This is the first study that investigated the general profile of intracellular and released neurotrophic factors and their receptors in human astrocytes and how this profile is altered by α-synuclein overexpression. (The present work was supported by the Research Fund of Istanbul University, Project no: 23616 and by the Scientific and Technological Research Council of Turkey-TUBITAK, Project no: 216S887.)