CNS & Neurological Disorders - Drug Targets - Volume 17, Issue 2, 2018

Background & Objective: The link between Zika Virus (ZIKV) epidemic and neurological disorder has raised an urgent global alarm. The current epidemic of ZIKV has triggered quick responses in the scientific world. The first case of ZIKV was reported in 2015 from Brazil and now has spread over 30 countries. Nearly four hundred cases of traveler associated ZIKV infection have also been reported in the United States. ZIKV is primarily transmitted by mosquito belonging to the genus Aedes that are widely distributed throughout the world. Additionally, the virus can also be transmitted from male to female by sexual contact. The epidemiological investigations during the current outbreak found a causal link between infection in pregnant women and the development of microcephaly (MCPH) in their unborn babies. This finding is a cause of grave concern since MCPH is a serious neural developmental disorder that can lead to significant post-natal developmental abnormalities and disabilities. Recently, published data indicates that ZIKV infection severely affects the growth of fetal neural progenitor cells and cerebral neurons resulting in malformation of cerebral cortex leading to MCPH. Recently, it has been reported that ZIKV infection deregulates the signaling pathway of neuronal cell and inhibits the neurogenesis. Conclusion: In this review, we discussed the information about cellular and molecular mechanisms of neurodegeneration of human neuronal cells and inhibition of neurogenesis. The provided information in this review will be very useful further not only in neuro-scientific research but also in the desig and development of management strategies for MCPH and other mosquito-borne diseases.

Background: Despite a wide variety of current analgesia regimens, chronic pain is an incredibly difficult condition to treat. Its pathophysiology, initiation, development and course involve a range of different receptors and transmitters. The acid-sensing ion channels (ASICs) are being attributed to an increasingly larger significance in pain aetiology. Over the last few years, the mechanism of ASICs action, influence of their antagonists/agonists and clinical applications have been well described. However, the importance of this protein is significantly larger, not only from the perspective of pain management, but also in psychiatry of addiction or fear. Recently discovered peptides from three-finger toxin group, called mambalgins (isolated from Dendroaspis polylepis polylepsis) exhibit potent analgesic mechanisms of action on ASICs in animal model. Aims & Methods: The article reviews current knowledge in the field of mambalgins and assesses their potential analgesic application, based on the recent experimental evidence. Results: The mambalgins seem to decrease the intensity of the inflammatory, neuropathic and mechanic pain. This has been demonstrated in animal studies of different pain models, including carrageenan- induced inflammatory pain, chronic constrictive injury-induced neuropathic pain and thermal pain. The mechanism of mambalgin action is not clearly defined, but it is suspected that they bind directly to the pH-sensitive region of the ASIC. Conclusion: In this short review, we attempted to summarise the current knowledge about mambalgins and their potential applications as a new substance in searching for the ideal analgesia without common side effects of the other drug groups.

Objective: To investigate growth factor changes in cerebrospinal fluid (CSF) of children with mental retardation (MR) before and after neural precursor cell transplantation (NPCT), in an attempt to provide experimental support for the clinical treatment of MR with NPCT. Methods: The study comprised of 28 MR children who received twice NPCT in our hospital. CSF was collected at both times of NPCT to assess growth factors by ELISA. In addition, the content of insulinlike growth factor 1 (IGF-1) in CSF was assayed to determine possible correlations between IGF-1 changes and the short-term therapeutic effect of NPCT. Results: Of all the growth factors detected in CSF, only IGF-1 was increased significantly after NPCT (P<0.05). Fifteen of the twenty-eight MR children achieved short-term therapeutic efficacy, whereby the content of IGF-1 after NPCT was significantly higher than that before NPCT (P<0.05). There was no difference in IGF-1 content before and after NPCT in the remaining 13 MR children without shortterm therapeutic effect (P=0.657). There was a significant difference in IGF-change between the two groups of patients (P<0.05). Conclusion: IGF-1 may be one of the mechanisms contributing to the therapeutic effect of NPCT.

Background & Objective: Adult neurogenesis, a specific form of brain plasticity in mammals that occurs in the subventricular zone, is subject to complex regulation. Hypocretin/orexin neurons are implicated in the regulation of sleep and arousal states, among other functions. Here we report for the first time the presence of orexinergic projections within the adult rat subventricular zone. Post-mortem retrograde tracing combined with immunofluorescence indicated orexinergic projections toward the subventricular zone. To establish the relationship between the depletion of orexin neurons and the number of proliferating cells in the subventricular zone, we labeled mitotic cells. Histological analysis revealed proliferating cells to be in close contact with orexinergic fibers. Neurotoxinlesioning of orexin neurons in the lateral hypothalamus significantly activated precursor cell proliferation in the subventricular zone. Furthermore, cell proliferation in both normal and lesioned animals failed to reveal newly born orexin neurons in the lateral hypothalamus. Conclusion: Based on these findings, we suggest that the adult subventricular zone is affected by orexinergic signaling, the functional implication of which must be further elucidated.

Background: Regulatory T-Cells (Treg Cells), as one of the immune system components, have been highly effective in the autoimmune diseases prevention, particularly multiple sclerosis (MS). Cytokine-based therapies such as interferon beta-1a (IFN-β1a) is a common drug in MS treatment; however, its exact mechanisms are insufficiently described. Objective: Therefore, the goal of this study was to evaluate the in vivo impact of IFN-β1a on the Treg Cells in MS. Methods: In this case-control study, Treg Cells were analysed by flowcytometry in IFN-β1a-treated relapsing-remitting MS (RRMS) in comparison with new cases of MS and healthy subjects. Results: The frequency of Treg Cells in the IFN-β1a treated-RRMS was increased compared to the new MS cases (P < 0.05). Furthermore, the MFIs of the CD4 and CD25 in T-Cells were significantly reduced in new cases of MS and IFN-β1a-treated RRMS than the control subjects (P < 0.05). Additionally, the FoxP3 MFIs in CD4 + CD25 + T-Cells of IFN-β1a-treated RRMS were significantly lower than the new cases of MS. Conclusion: Overall, the present study indicated that IFN-β1a as an immunomodulatory drug led to an enhancement in Treg Cells population without CD4, CD25, and FoxP3 molecules upregulation in Treg Cells.

Background & Objective: Aging is characterized by gradual accumulation of macromolecular damage leading to progressive loss of physiological function and increased susceptibility to diverse diseases. Effective anti-aging strategies involving caloric restriction or antioxidant supplementation are receiving growing attention to attenuate macromolecular damage in age associated pathology. Method: In the present study, we for the first time investigated the effect of quercetin, caloric restriction and combined treatment (caloric restriction with quercetin) on oxidative stress parameters, acetylcholinesterase and ATPases enzyme activities in the cerebral cortex of aged male Wistar rats. 21 months aged rats were divided into four groups (n=6-8) such as group 1-fed ad libitum (AL); group 2-quercetin supplementation of 50 mg/kg b.w/day for 45 days fed ad libitum (QUER); group 3: caloric restricted (CR) (fed 40% reduced AL for 45 days); group 4-fed 40% CR and 50 mg/kg b.w/day QUER for 45 days (CR + QUER). Group 5-three month age old rats served as young control (YOUNG). Results: Our results demonstrate that combined treatment of caloric restriction and quercetin significantly improved the age associated decline in the activities of endogenous antioxidant enzymes [such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)] and glutathione (GSH) content and attenuated elevated levels of protein carbonyl content (PCC), lipid peroxidation, lipofuscin, reactive oxygen species (ROS), and nitric oxide (NO). Furthermore, it is also observed that combined treatment ameliorated age associated alterations in acetylcholine esterase (AChE) and adenosine triphosphatases (ATPases) such as Na+/K+-ATPase and Ca+2-ATPase (but not Mg+2- ATPase) enzyme activities. Conclusion: Finally, we conclude that combined treatment of caloric restriction and quercetin (but not either treatment alone) in late life is an effective anti-aging therapy to counteract the age related accumulation of oxidative macromolecular damage.

Background & Objective: Aroclor 1254 is a widespread toxic compound of Polychlorinated Biphenyls (PCBs), which can create significant nervous problems. No remedies have been found to date. The aim of this study was to reveal the damage that occurs in the central nervous system of rat pups exposed to Aroclor 1254 in the prenatal period and to show the inhibiting effect of curcumin, which is a strong anti-oxidant and neuroprotective substance. Method: The study established 3 groups of adult female and male Wistar albino rats. The rats were mated within these groups and the offspring rats were evaluated within the group given Aroclor 1254 only (n=10) and the group was given both Aroclor 1254 and curcumin (n=10) and the control group (n=10). The groups were compared in respect of pathomorphological damage. The immunohistochemical evaluation was made of 8-hydroxdeoxyguanosine (8-OHdG), 4-hydroxynoneal (4HNE), myelin basic protein (MBP) expressions and TUNEL reaction. The biochemical evaluation was made of the changes in the TAS-TOS and Neuron Specific Enolase (NSE) levels. Damage was seen to have been reduced with curcumin in the 8OHdG and TUNEL reactions, especially in the forebrain and the midbrain, although the dosage applied did not significantly change TAS and TOS levels. Consequently, it was understood that Aroclor 1254 caused damage in the central nervous system of the pup in the prenatal period, and curcumin reduced these negative effects, particularly in the forebrain and the midbrain. Conclusion: It was concluded that curcumin could be a potential neuroprotective agent and would be more effective at higher doses.

Background: Trans-Sinapic Acid is a bioactive compound. Recent studies showed that it has a significant potential to attenuate various chemically induced Neurodegenerative toxicities. Aim: The present study investigates the potential of trans-Sinapic Acid as neuromodulator and its effect on release of Monoamine Oxidase (MAO-A, MAO-B), TNF-α, Acetylcholine esterase Enzyme, in cognitive dysfunctions associated with experimental dementia. Experiment: Aluminium chloride was administered at a dose of 175mg/kg, p.o. for a period of 25 days in rats and then divided into different groups, i.e. Treatment group, negative control and two groups of trans- Sinapic Acid, (at a dose of 30 and 60mg/kg, p.o.), where these groups treated and observed until the 35th day of experimental trial. Morris water Maze (MWM) and Photoactometer was used to access learning, memory and ambulatory movements on 5th, 16th, 26th and 36th day of experiment. Later, the animals were sacrificed for biochemical and histopahological studies. The oxidative stress was measured by estimating the levels of Glutathion (GSH), Superoxide dismutase (SOD), Nitrite, Catalase. Brain acetylcholine esterase (Ache) activity and Monoamine oxidase (MAO-A, MAO-B) were also estimated. The Brain level of TNF-α was measured as a marker of inflammation. Results: Aluminium chloride (AlCl3) produced a marked decline in MWM performance and ambulatory movements' of animals, reflecting impairment of memory and learning. Trans-Sinapic Acid treatment significantly modulates AlCl3 induced memory deficits, biochemical and pathological alterations. The findings demonstrate that the memory restorative ability of trans-Sinapic Acid may be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory potential.