CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 19, Issue 1, 2020

Epilepsy is a neurological disorder that involves abnormal and recurrent neuronal discharges, producing epileptic seizures. Recently, it has been proposed that the Wnt signaling pathway is essential for the central nervous system development and function because it modulates important processes such as hippocampal neurogenesis, synaptic clefting, and mitochondrial regulation. Wnt/β- catenin signaling regulates changes induced by epileptic seizures, including neuronal death. Several genetic studies associate Wnt/β-catenin signaling with neuronal excitability and epileptic activity. Mutations and chromosomal defects underlying syndromic or inherited epileptic seizures have been identified. However, genetic factors underlying the susceptibility of an individual to develop epileptic seizures have not been fully studied yet. In this review, we describe the genes involved in neuronal excitability in epileptogenic zones dependent on the Wnt/β-catenin pathway.

Background and Objective: Madecassic Acid (MA) is well known to induce neurite elongation. However, its correlation with the expression of fast transient potassium (AKv) channels during neuronal development has not been well studied. Therefore, the present study was designed to investigate the effects of MA on the modulation of AKv channels during neurite outgrowth. Methods: Neurite outgrowth was measured with morphometry software, and Kv4 currents were recorded by using the patch clamp technique. Results: The ability of MA to promote neurite outgrowth is dose-dependent and was blocked by using the mitogen/extracellular signal-regulated kinase (MEK) inhibitor U0126. MA reduced the peak current density and surface expression of the AKv channel Kv4.2 with or without the presence of NaN3. The surface expression of Kv4.2 channels was also reduced after MA treatment of growing neurons. Ethylene glycol tetraacetic acid (EGTA) and an N-methyl-D-aspartate (NMDA) receptor blocker, MK801 along with MA prevented the effect of MA on neurite length, indicating that calcium entry through NMDA receptors is necessary for MA-induced neurite outgrowth. Conclusion: The data demonstrated that MA increased neurite outgrowth by internalizing AKv channels in neurons. Any alterations in the precise density of ion channels can lead to deleterious consequences on health because it changes the electrical and mechanical function of a neuron or a cell. Modulating ion channel’s density is exciting research in order to develop novel drugs for the therapeutic treatment of various diseases of CNS.

Background: The activity of the Hypothalamic-Pituitary-Adrenal (HPA) axis is commonly dysregulated in stress-related psychiatric disorders. Annexin A1 (ANXA1), an endogenous ligand of Formyl Peptide Receptor (FPR) 2/3, is a member of the family of phospholipid- and calcium-binding proteins with a well-defined role in the delayed early inhibitory feedback of Glucocorticoids (GC) in the pituitary gland and implicated in the occurrence of behavioural disorders such as anxiety. Objective: The present study aimed to evaluate the potential role of ANXA1 and its main receptor, as a cellular mediator of behavioural disorders, in a model of Corticosterone (CORT)-induced depression and subsequently, the possible correlation between the depressive state and impairment of hippocampal memory. Methods: To induce the depression model, Wild-Type (WT), ANXA1 Knockout (KO), and FPR2/3 KO mice were exposed to oral administration of CORT for 28 days dissolved in drinking water. Following this, histological, biochemical and behavioural analyses were performed. Results: FPR2/3 KO and ANXA1 KO mice showed improvement in anxiety and depression-like behaviour compared with WT mice after CORT administration. In addition, FPR2/3 KO and ANXA1 KO mice showed a reduction in histological alterations and neuronal death in hippocampal sections. Moreover, CORT+ FPR2/3 KO and ANXA1 KO, exhibited a higher expression of Brain-Derived Neurotrophic Factor (BDNF), phospho-ERK, cAMP response element-binding protein (pCREB) and a decrease in Serotonin Transporter Expression (SERT) compared to WT(CORT+) mice. Conclusion: In conclusion, the absence of the ANXA1 protein, even more than the absence of its main receptor (FPR 2/3), was fundamental to the inhibitory action of GC on the HPA axis; it also maintained the hippocampal homeostasis by preventing neuronal damage associated with depression.

Background: Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of inflammatory and immune-regulatory cytokines and stimulation of indoleamine-2,3-dioxygenase (IDO). There is also evidence that anti-inflammatory drugs may have clinical efficacy in MDD. Methods: This study examined a) IDO in association with interferon (IFN)-γ, Interleukin (IL)-4 and Transforming Growth Factor (TGF)-β1 in 140 drug-naïve MDD patients and 40 normal controls; and b) the effects of an eight-week treatment of sertraline with or without ketoprofen (a nonsteroidal antiinflammatory drug) on the same biomarkers in 44 MDD patients. Results: Baseline IDO, IFN-γ, TGF-β1 and IL-4 were significantly higher in MDD patients as compared with controls. Treatment with sertraline with or without ketoprofen significantly reduced the baseline levels of all biomarkers to levels which were in the normal range (IDO, TGF-β1, and IL-4) or still somewhat higher than in controls (IFN-γ). Ketoprofen add-on had a significantly greater effect on IDO as compared with placebo. The reductions in IDO, IL-4, and TGF-β1 during treatment were significantly associated with those in the BDI-II. Conclusion: MDD is accompanied by activated immune-inflammatory pathways (including IDO) and the Compensatory Immune-Regulatory System (CIRS). The clinical efficacy of antidepressant treatment may be ascribed at least in part to decrements in IDO and the immune-inflammatory response. These treatments also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD while enhancing the CIRS.

Background & Objective: The pharmacokinetics and acute toxicity of a histone deacetylase inhibitor, Scriptaid, was unknown in the mouse. The aim of this study was to determine the pharmacokinetics, acute toxicity, and tissue distribution of Scriptaid, a new histone deacetylase inhibitor, in mice, and its neuroprotective efficacy in a mouse intracranial hemorrhage (ICH) model. Methods: The pharmacokinetics, acute toxicity, and tissue distribution were determined in C57BL/6 male and female mice after the intraperitoneal administration of a single dose. Behavioral tests, as well as investigations of brain atrophy and white matter injury, were used to evaluate the neuroprotective effect of Scriptaid after ICH. Western blotting was used to investigate if Scriptaid could offer antiinflammatory benefits after ICH. Results: No significant differences were observed in body weight or brain histopathology between the group that received Scriptaid at 50 mg/kg and the group that received dimethyl sulfoxide (control). The pharmacokinetics of Scriptaid in mice was nonlinear, and it was cleared rapidly at low doses and slowly at higher doses. Consistent with the pharmacokinetic data, Scriptaid was found to distribute in several tissues, including the spleen and kidneys. In the ICH model, we found that Scriptaid could reduce neurological deficits, brain atrophy, and white matter injury in a dose-dependent manner. Western blotting results demonstrated that Scriptaid could decrease the expression of pro-inflammatory cytokines IL1β and TNFα, as well as iNOS, after ICH. Conclusion: These findings indicate that Scriptaid is safe and can alleviate brain injury after ICH, thereby providing a foundation for the pharmacological action of Scriptaid in the treatment of brain injury after ICH.

Background: Brain-Derived Neurotrophic Factor (BDNF) plays critical roles during development of the central and peripheral nervous systems, as well as in neuronal survival after injury. Although proBDNF induces neuronal apoptosis after injury in vivo, whether it can also act as a death factor in vitro and in vivo under physiological conditions and after nerve injury, as well as its mechanism of inducing apoptosis, is still unclear. Objective: In this study, we investigated the mechanisms by which proBDNF causes apoptosis in sensory neurons and Satellite Glial Cells (SGCs) in Dorsal Root Ganglia (DRG) After Sciatic Nerve Transection (SNT). Methods: SGCs cultures were prepared and a scratch model was established to analyze the role of proBDNF in sensory neurons and SGCs in DRG following SNT. Following treatment with proBDNF antiserum, TUNEL and immunohistochemistry staining were used to detect the expression of Glial Fibrillary Acidic Protein (GFAP) and Calcitonin Gene-Related Peptide (CGRP) in DRG tissue; immunocytochemistry and Cell Counting Kit-8 (CCK8) assay were used to detect GFAP expression and cell viability of SGCs, respectively. RT-qPCR, western blot, and ELISA were used to measure mRNA and protein levels, respectively, of key factors in BDNF-TrkB, proBDNF-p75NTR/sortilin, and apoptosis signaling pathways. Results: proBDNF induced mitochondrial apoptosis of SGCs and neurons by modulating BDNF-TrkB and proBDNF-p75NTR/sortilin signaling pathways. In addition, neuroprotection was achieved by inhibiting the biological activity of endogenous proBDNF protein by injection of anti-proBDNF serum. Furthermore, the anti-proBDNF serum inhibited the activation of SGCs and promoted their proliferation. Conclusion: proBDNF induced apoptosis in SGCs and sensory neurons in DRG following SNT. The proBDNF signaling pathway is a potential novel therapeutic target for reducing sensory neuron and SGCs loss following peripheral nerve injury.