CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 16, Issue 7, 2017

Background: Generation of nascent functional neurons from neural stem cells in the adult brain has recently become largely accepted by the neuroscience community. In adult mammals including humans, the process of neurogenesis has been well documented in two brain regions; the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. Method: Some evidence has indicated neurogenesis in other regions of the adult mammalian brain such as the neocortex, cerebellum, striatum, amygdala and hypothalamus. These discoveries question a long standing dogma on nervous system regeneration and provide medical science with potential new strategies to harness the process of neurogenesis for treating neurological disabilities and neurodegenerative diseases. Conclusion: In this current review, we address the most recent advances on the role of neurogenesis in the adult brain and therapeutic potential in the two most common neurodegenerative disorders, Parkinson's and Alzheimer's diseases.

Background & Objective: Epilepsy is one of the most complex neurological disorders and its study requires a broad knowledge of neurology and neuroscience. It comprises a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures, and are often accompanied by cognitive deficits and mood disorder. This condition is one of the most common neurological disorders. Until recently, alterations of neuronal activities had been the focus of epilepsy research. This neurocentric emphasis did not address issues that arise in more complex models of epileptogenesis. An important factor in epilepsy that is not regulated directly by neurons is inflammation and the immune response of the brain. Recent evidence obtained in rodent epilepsy models supports the role of immune responses in the initiation and maintenance of epilepsy. Recognition of exogenous pathogens by the innate immune system is mediated by some pattern recognition receptors such as Toll-like receptors leading to cell activation and cytokine production. Currently, these receptors have been the focus of epilepsy studies looking to determine whether the innate immune activation is neuroprotective or neurotoxic for the brain. Conclusion: Here, we present the evidence in the literature of the involvement of key innate immune receptors in the development of epilepsy. We address some of the contradictory findings in these studies and also mention possible avenues for research into epilepsy treatments that target these receptors.

Background & Objective: Multiple classes of natural products, such as antiandrogens or steroids have been used as antioxidants and anti-inflammatory treatments in neurodegenerative diseases. This paper aims to review current knowledge on these substances and their possible relationship with free radicals as an alternative therapy and prevention of common neurological disorders. An exhaustive review of the neurochemical mechanisms of these substances in the central nervous system of humans and animal models is yet to be undertaken in the literature, particularly regarding their importance and increasing use. Conclusion: Androgen receptor antagonists act in a different way that may underlie the benefits of natural products, with the expectation that in adults, neurological disorders would respond to natural antiandrogens. We hope that this work would provide valuable insight into the protective and therapeutic roles for natural antiandrogens and steroids in common neurological disorders.

Background: Epilepsy is one of the most common neurological disorders in humans, and the role of the cerebellum in its physiopathology remains the subject of study. The Purkinje cells (PC), whose axons target the dentate and interpositus nuclei, form the main cerebellar output to forebrain structures involved in epilepsy. Cerebellar atrophy related to loss of PC has been reported in chronic epilepsy although its mechanism remains unclear. Taking into account that an overexpression of β-Catenin has been related with cell death, here we present the signaling of β-Catenin and the type of PC death in cerebellum of rats with seizures induced by the amygdaloid kindling model. Method: Using an immunohistochemistry and western blot assay for β-Catenin, c-Myc, cyclin D3, TUNEL and caspase-3, in rats chronically implanted with electrodes, receiving 0, 3, 15, and 45 electrical stimuli. Results: We found that such rats suffering a major number of stimuli showed the highest amount of marks assessed. Conclusion: We concluded that there is a higher activity of the Wnt/β-Catenin pathway associated with increased number of stimuli may be related with the presence of apoptosis in the cerebellum treated with amygdala kindling. In this way, we suggest this pathway as one of the mechanisms by which cerebellar neurons death in generalized seizures.

Background: Cerebral small vessel diseases (CSVDs) always coincide with endothelial dysfunction and blood-brain barrier (BBB) damage. However, the detailed mechanisms of CSVD are still unclear and the therapeutic efficacy is not so satisfaction. Granulocyte-colony stimulating factor (G-CSF) can play a neuroprotective role in many neurological diseases. We investigated whether G-CSF exerted positive effects on BBB protection and cognitive function improvement in spontaneously hypertensive rats (SHRs), a rat model displaying the early histopathological changes of CSVD. Method: Twenty-four-week-old SHRs received daily administrations of either G-CSF (50μg/kg) or normal saline (NS) for 7 days. The novel object recognition test (NORT) was then conducted after treatment. After behavioral test, we examined IgG fluorescence staining to indicate BBB leakage. G-CSF receptor (G-CSFR), aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) expression were determined by immunofluorescence. The surface structure of endothelial cells was examined by scanning electron microscopy (SEM). Results: G-CSF significantly attenuated IgG leakage and improved non-spatial memory in SHRs. G-CSFR was expressed at higher levels in both G-CSF-SHRs and NS-SHRs. The surface structural changed on the endothelial cells and expression of AQP-4 and GFAP decreased after G-CSF treatment. However, no significant differences in Claudin-5 expression were observed. Conclusion: These findings demonstrated that the administration of exogenous G-CSF can improve cognitive function in a model of CSVD, possibly due to the recovery of endothelial and BBB function.

Introduction: There is an unmet need to develop better treatments for acute ischemic stroke (AIS). Desmoteplase is a vampire bat saliva-derived analogue of human tissue plasminogen activator. It has higher fibrin selectivity and a longer half-life, compared to alteplase. We performed this metaanalysis to investigate the safety and efficacy of desmoteplase in AIS. Method: A computer literature search (PubMed, EMBASE, CENTRAL, Scopus, Web of science, and clinicaltrials.gov) was carried out. Data were extracted from eligible records and analyzed using RevMan software (version 5.3 for windows). Safety and efficacy endpoints were pooled as odds ratios (ORs) for the two groups. Result: Five randomized trials (n=821 patients) were pooled in the final analysis. The overall effect size favored desmoteplase over placebo in terms of reperfusion 4 to 24 hours posttreatment (OR 1.49, 95% CI [1.02, 2.19]). However, the pooled effect size did not favor either of the two groups in terms of good clinical outcome at 90 days (OR 1.16, 95% CI [0.86, 1.55]). Neither of the primary safety outcomes differed significantly between the two groups (symptomatic intracranial hemorrhage: OR 1.29, 95% CI [0.53, 3.16] and mortality within 90 days: OR 1.20, 95% CI [0.73, 1.97]). Conclusion: Current evidence suggests a favorable reperfusion effect for desmoteplase within 3 to 9 hours after AIS. Further large randomized trials, using a moderate dose between 90 μg/kg and 125 μg/kg, are required to translate this successful reperfusion into better clinical and quality of life outcomes for AIS patients.

Background: Alzheimer's disease (AD) therapy is based on several natural and synthetic compounds that act as acetylcholinesterase (AChE) and N-methyl-D-aspartate receptor (NMDA) ligands that have limited efficiency in relieving AD symptoms. Recent studies show that inhibitors isolated from Mentha spicata L. subsp. spicata are promising for AD therapy. Objective: We aimed to identify novel and more potent phytopharmaceutical compounds for AD treatment by taking into account the compounds from Mentha spicata L. subsp. spicata essential oil. Method: We generated structure-activity relationship (SAR) models that predict the biological activities of 14 Mentha spicata L. subsp. spicata compounds on AChE and NMDA by comparing their molecular features with those of the three conventional ligands: donepezil, galantamine and memantine. Results: The most relevant descriptors for predicting the biological activities of considered compounds are solvent accessible area and their subdivided, hydrophobicity, energy of frontier molecular orbitals and counts of the aromatic ring and rotatable bounds. 1,8-cineole, the main compound from Mentha spicata L. subsp. spicata essential oil, resulted to be similar with memantine and dissimilar with donepezil in respect to hidrophobicity (logP1,8-cineole=2.95, logPmemantine=2.81, logPdonepezil=4.11), the energy of LUMO (eLUMO1,8-cineole=3.01 eV, eLUMOmemantine=3.35 eV, eLUMOdonepezil=-0.35 eV) and the solvent accessible surface areas over all hydrophobic (SA_H1,8-cineole= 350 Å2, SA_Hmemantine= 358 Å2, SA_Hdonepezil= 655 Å2) or polar atoms (SA_P1,8-cineole= 4 Å2, SA_Pmemantine=10 Å2, SA_Pdonepezil=44.62 Å2). Conclusion: Our results point towards 1,8-cineole as a good candidate for NMDA antagonism, with a weaker AChE inhibitory effect. Our results may be useful in establishing new therapeutic strategies for neurological disorders.

Background & Objective: Down syndrome, a genetic condition caused by triplication of chromosome 21, is characterized by widespread neurogenesis reduction and cognitive impairment. Unlike other brain functions, smell is not impaired at early life stages and olfactory deterioration begins to appear in adulthood. Similarly to individuals with Down syndrome, in the Ts65Dn mouse model of Down syndrome smell function is normal at early life stages. Smell impairment only appears in adulthood associated with a reduction in the number of new granule neurons migrated to the olfactory bulb from the subventricular zone. Based on evidence that lithium positively impacts neurogenesis, the goal of current study was to establish whether treatment with lithium restores olfactory bulb neurogenesis and olfactory performance in middle-aged Ts65Dn mice. Method: Euploid and Ts65Dn mice aged 13 months were treated with lithium chow or control chow for one month. Before the end of treatment, mice were injected with BrdU, in order to label proliferating cells. Results showed that in Ts65Dn mice lithium treatment restored the number of neural precursor cells in the subventricular zone of the lateral ventricle, rostral migratory stream and olfactory bulb. This effect was accompanied by restoration of olfactory performance. Unlike in olfactory neurogenic regions, treatment had no neurogenesis-enhancing effect on the subgranular zone of the hippocampal dentate gyrus, indicating that lithium has no generalized positive effect on the brain. Conclusion: Results suggest that lithium may have a positive impact in brain disorders that, similarly to Down syndrome, are characterized by olfactory decline and neurogenesis impairment in the subventricular zone.

Background: Selective butyrylcholinesterase (BuChE)-inhibition, increases acetylcholine (ACh) levels. In rodents, this inhibition is known to boost cognition. Also, this occurs without the typical unwanted adverse effects of acetylcholinesterase-inhibitors or AChE-Is. The novel compound, fluorobenzylcymserine (FBC), is derived from our effort to design a selective BuChE-inhibitor. Also, we wanted to check whether butyrylcholinesterase-inhibitors (BuChE-Is) possessed an edge over AChE-Is in Alzheimer's disease (AD) in terms of efficacy and/or tolerance. Method: FBC was synthesized as reported earlier while enzymatic activity of BuChE was calculated by Ellman-technique. Molecular docking was performed using Autodock4.2. We applied classical as well as innovative analyses of enzyme-kinetics for exploring “FBC:human BuChE-interaction”. The mode of inhibition and kinetic parameters were also determined. Results: Docking results displayed two strong interacting sites for FBC. One of these binding sites was previously identified as a deep narrow groove having polar aromatic residues while a second site was identified during this study which displayed better interaction and was lined with aliphatic and sulphur containing residues. At low concentrations of BuChE, the IC50 was found to be very low i.e. 4.79 and 6.10 nM for 12 and 36 μg, respectively, whereas it increased exponentially by increasing the units of BuChE. Conclusion: These analyses indicate that FBC is an interesting AD drug candidate that could provide a potent and partial mixed type of inhibition of human BuChE.

Background: Brain-derived neurotrophic factor (BDNF) plays a crucial role in promoting survival and differentiation of neurons and neural stem cells (NSCs), but the downstream regulating mechanisms remain poorly understood. Objective: We investigated whether BDNF exerts its effect by triggering the phosphoinositide 3-kinase (PI3K), protein kinase B, PKB (AKT), glycogen synthase kinase-3β (GSK-3β) and β-catenin signaling pathway in cultured neurons and NSCs derived from the rat embryonic spinal cord. Method: Immunocytochemistry was used to detect neuronal and NSCs characteristics. RT-PCR was used to detect PI3K/AKT/GSK3β/β-catenin pathway expression. Results: Neurons and NSCs were successfully separated and cultured from Sprague-Dawley rat embryonic spinal cord and were respectively labeled using immunocytochemistry. Neuron-specific nuclear protein, neuronal class III β-tubulin, and neurofilament expression were detected in neurons; nestin, glial fibrillary acidic protein, microtubule-associated protein 2 and chondroitin sulfate glycosaminoglycan expression were detected in the NSCs. BDNF promoted significant neuronal growth (number, soma size, and average neurite length), as well as NSCs proliferation and differentiation, but BDNF antibody decreased neuronal growth and NSCs proliferation and differentiation. RT-PCR was used to detect changes in BDNF signal pathway components, showing that BDNF upregulated tropomyosin receptor kinase B, phosphoinositide 3-kinase (PI3K), AKT and β-catenin, but downregulated GSK-3β in the neurons and NSCs. BDNF antibody downregulated BDNF, tropomyosin receptor kinase B, PI3K, AKT, β-catenin and cellular-myelocytomatosis viral oncogene, but upregulated GSK- 3β, in the neurons and NSCs. Conclusion: Our findings suggested that BDNF contributed to neuronal growth and proliferation and differentiation of NSCs in vitro by stimulating PI3K/AKT/GSK3β/β-catenin pathways.

Background: Depressive disorders are associated with oxidative stress. Therefore, it is interesting if antidepressants can affect redox equilibrium and signaling. The first step of our study was to determine the influence of the adenosine system on the antidepressant-like activity of noncompetitive antagonist of the NMDA (N-methyl-d-aspartate) receptor complex – dizocilpine (MK- 801). To this aim, two behavioral tests commonly used to assess the antidepressant capability of drugs – the forced swim test (FST) and tail suspension test (TST), were performed. Locomotor activity was estimated to verify and exclude false positive/negative results in the FST and TST. To examine whether antidepressants affect redox equilibrium, we have investigated lipid peroxidation products (LPO), GSH (glutathione), GSSG (glutathione disulfide), NADP+ (nicotinamide adenine dinucleotide phosphate) and NADPH (reduced nicotinamide adenine dinucleotide phosphate) in the cerebral cortex of mice following administration of CPT (8-cyclopentyl-1,3-dimethylxanthine) and MK-801 (dizocilpine) under environmental stress conditions. Method: The experiments were carried out using male Albino Swiss mice (25-30 g). The drugs were administered ip., alone and simultaneously, 60 min before tests. Results: The behavioural tests results showed that CPT (3 mg/kg) potentiated the antidepressant-like activity of MK-801 (0.05 mg/kg) and the observed effects were not due to the increase in mice locomotor activity. Positive synergism of CPT and MK-801 in reduction of environmental stress conditions was revealed. In this group an increase in GSH and GSSG without changes in GSH/GSSG ratio and reduction of LPO was found. The level of lipid peroxidation products was also decreased in group receiving CPT and MK-801 separately. Conclusion: Examined antidepressant agents may increase antioxidant defences however further studies are needed with different range of time.

Background & Objective: Ketamine, a noncompetitive NMDA receptor antagonist, exhibits rapid antidepressant actions, but the underlying mechanism remains obscure. AMPA receptor and cAMP response element-binding protein (CREB) are involved in the antidepressant actions of Ketamine and imipramine, a traditional tricyclic antidepressant. However, ketamine exerts its therapeutic actions much faster than imipramine. Understanding the discrepancy of antidepressant efficiency between ketamine and the traditional antidepressant is important for elucidating the mechanism underlying ketamine’s fast-acting antidepressant responses as well as designing new rapid antidepressants. Results: Here we show that the enhancement of the phosphorylation of CREB Ser133 and expression of CREB and glutamate receptor 1 (GluR1) are necessary for both ketamine’s and imipramine's antidepressant actions, but the enhancements at early stage may account for the faster onset of ketamine's antidepressant action than imipramine. Notably, ketamine but not imipramine enhances CREBregulated transcription coactivator-1 (CRTC1) expression and induces potentiation of excitatory synaptic transmission at Schaffer collateral CA1 synapses, which indicates critical targets for unveiling ketamine's rapid antidepressant actions. Conclusion: Our study suggests that differential regulation of CRTC1 expression may contribute to the discrepancy of antidepressant efficacy between ketamine and imipramine, which may lead to a better understanding of ketamine's fast antidepressant responses.