CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 18, Issue 2, 2019

Background & Objective: Depression, a risk factor for several serious diseases, is a highly prevalent and life-threatening psychiatric disorder. It can affect the individual’s position in life and reduce the living standards. The research on the use of medicinal plants in treating this disease has increased enormously because of the possible low rehabilitation rate and side effects of available synthetic drugs, such as sexual dysfunction, nausea, fatigue, insomnia, hypersomnia, and weight gain. Conclusion: Therefore, this review aimed to draw attention to the antidepressant effects of culinary herbs and traditional medicinal plants and their active components, thereby promoting their use in the development of more potent antidepressants with improved side effect profile.

Background & Objective: Alzheimer’s disease (AD) and Parkinson’s disease (PD) affect an increasing number of the elderly population worldwide. The existing treatments mainly improve the core symptoms of AD and PD in a temporary manner and cause alarming side effects. Naturally occurring flavonoids are well-documented for neuroprotective and neurorestorative effects against various neurodegenerative diseases. Thus, we analyzed the pharmacokinetics of eight potent natural products flavonoids for the druggability and discussed the neuroprotective and neurorestorative effects and the underlying mechanisms. Conclusion: This review provides valuable clues for the development of novel therapeutics against neurodegenerative diseases.

Background: Xuesaitong mainly comprises Panax notoginseng saponins and has shown a promising feature in an acute ischemic stroke model; however, its effect on long-term recovery following stroke, and the related mechanisms, are unknown. Methods: The objective of this study was to investigate the long-term protective effects of xuesaitong against ischemic stroke and its effect on microglial polarization. Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 45 min, and C57BL/6 mice were immediately injected with xuesaitong or vehicle through the caudal vein at the onset of cerebral reperfusion consecutively for 14 days. The animals were randomly divided into three groups: a sham-operated group, vehicle-treated group and xuesaitong-treated group at a dose of 15μg/g. Subsequently, 2,3,5-triphenyltetrazolium chloride staining was used to assess infarct volume, and adhesive removal tests and balance beam tests were used to evaluate neurological deficits at days 1, 3, 7 and 14 following ischemia. Reverse-transcriptase polymerase chain reaction and immunofluorescence staining for M1 markers (CD16, iNOS) and M2 markers (CD206, arginase-1) were performed to characterize phenotypic changes in microglia. Elisa was used to determine the release of pro-inflammatory and anti-inflammatory cytokines. TUNEL staining was conducted to detect neuronal cell apoptosis, and western blots were used to determine the activation of signal transducer and activator of transcription 3 (STAT3). Results: Our results revealed that xuesaitong treatment, compared with vehicle treatment, significantly reduced cerebral infarct volume 1 and 3 days after MCAO and resulted in significant improvements in long-term neurological outcomes. Furthermore, xuesaitong treatment, compared with vehicle treatment, significantly reduced M1 markers and elevated M2 markers 7 and 14 days after MCAO at both the mRNA and protein level in ipsilateral brain tissue. This finding was also accompanied by a reduction in neuronal cell apoptosis and p-STAT3 transcription factor levels in the xuesaitong-treated group compared with the vehicle-treated group. Conclusion: We demonstrated that xuesaitong has long-term neuroprotective effects against ischemic stroke, possibly by promoting the polarization of microglia to an M2 phenotype and by inhibiting neuronal cell death via down-regulation of the STAT3 signaling pathway, providing new evidence that xuesaitong might be a promising therapeutic strategy for ischemic stroke.

Objective: Recently, we reported that stable-phase schizophrenia is characterized by two interrelated symptom dimensions: PHEMN (psychotic, hostility, excitation, mannerism and negative symptoms); and DAPS (depressive, anxiety and physio-somatic symptoms) and that Major Neuro-Cognitive psychosis (MNP) is the full-blown phenotype of schizophrenia (largely overlapping with deficit schizophrenia). Herein we examined the effects of immune activation in association with tryptophan catabolite (TRYCAT) patterning and memory disorders on PHEMN/DAPS dimensions and MNP. Methods: Serum levels of macrophage inflammatory protein-1 (MIP-1), soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), IL-10, eotaxin, IgA/IgM responses to TRYCATs, and Consortium to Establish a Registry for Alzheimer’s disease (CERAD) tests were assessed in 40 controls and 80 schizophrenia patients. Results: Schizophrenia and MNP were predicted by significantly increased levels of IL-10, eotaxin and TRYCATs. A large part of variance in both PHEMN/DAPS symptom dimensions (42.8%) was explained by cytokine levels and TRYCATs combined. The MIP+sIL-1RA+IL-10 composite score and eotaxin explained each around on the basis of 19% of the variance in symptom dimensions, and approximately 18% of memory deficits. Moreover, MIP+sIL-1RA+IL-10 was significantly associated with elevations in picolinic acid, xanthurenic acid and 3-OH-kynurenine. Partial Least Squares path modeling shows that highly significant effects of MIP+sIL-1RA+IL-10 on symptomatology are mediated by the effects of noxious TRYCATs on memory deficits. Conclusion: Current findings indicate that in schizophrenia, immune activation may underpin activation of indoleamine-2,3-dioxygenase and kynurenine monooxygenase, while impairments in episodic and semantic memory may be caused by the neurotoxic effects of TRYCATs and eotaxin. The combined effects of immune activation, eotaxin and memory defects determine to a large extent, PHEMN/DAPS symptoms and the MNP phenotype. These findings indicate that schizophrenia phenomenology is largely mediated by multiple neuro-immune pathways and that immune activation, increased production of eotaxin and neurotoxic TRYCATs (picolinic acid, xanthurenic acid and 3-HOkynurenine) are new drug targets in schizophrenia and MNP.

Background & Objective: Chemokines and their receptors play a pivotal role in the pathogenesis of various autoimmune diseases such as multiple sclerosis, infectious diseases, and also in cancer metastasis via attraction of the pathogenic immune cells into the inflammation sites. Methods: Inflammatory chemokine CXCL10 as a T helper (Th)1-chemokine directs chemotaxis of many cell subsets especially Th1 into the central nervous system (CNS) via its receptor CXCR3 and it has been put forward as a potential therapeutic target in the treatment of multiple sclerosis. Nanobodies are the smallest intact antigen binding fragments derived from heavy chain-only antibodies occurring in camelids with unique biochemical and biophysical features which render them superior to conventional antibodies or antibody fragments. Here, we describe the generation, selection, and characterization of CXCL10-specific Nanobodies from camel immunized with CXCL10. The obtained Nanobodies displayed high affinity towards CXCL10 about 10-11-10-8 M. Results: Then a Nanobody with the highest affinity named 3Nb12 was selected and investigated as a migration inhibitor of CXCR3+ cells. Chemotaxis assay results showed that 3Nb12 blocked CXCL10- CXCR3 binding and potently inhibited chemotaxis of CXCR3-transfected HEK293T cells. Conclusion: The nanobody 3Nb12 might be a promising specific and powerful blocking agent of CXCL10 function, which can be used for diagnostic, therapeutic and research purposes in MS.

Background & Objective: The purpose of this study was to measure the effect on brain biomarkers after treatment with anticancer compounds - cytarabine (CT) and ferric carboxymaltose (FC) (Fe+3) in Wistar rats. Methods: The Wistar rats were treated as follows: group 1 (control), NaCl 0.9%; group 2, CT (25 mg/k), group 3, FC(Fe+3) (50 mg/k) and group 4, CT + FC(Fe+3). The animals were sacrificed and their brains were obtained and used to measure lipoperoxidation (TBARS), H2O2, Na+, K+ ATPase, glutathione (GSH), serotonin metabolite (5-HIAA) and dopamine. The results indicated an enhancement of lipid peroxidation in the cortex and striatum of groups treated with FC(Fe+3) and CT, while GSH decreased in the cortex of group treated with CT + FC(Fe+3). Dopamine decreased in the cortex of the rats that received CT, while in the striatum, 5HIAA increased in all groups. Results & Conclusion: These results suggest that the treatment with CT and FC(Fe+3) boosted oxidative stress and led to an alteration in momoamine concentrations in the brain.

Background & Objective: This study investigated the effects of ferulic acid (FR), muscle exercise (Ex) and combination of them on rotenone (Rot)-induced Parkinson disease (PD) in mice as well as their underlying mechanisms. Method: 56 male C57BL/6 mice were allocated into 8 equal groups, 1) Normal control (CTL), 2) FR (mice received FR at 20 mg/kg/day), 3) Ex (mice received swimming Ex) and 4) Ex + FR (mice received FR and Ex), 5) Rot (mice received Rot 3 mg/Kg i.p. for 70 days), 6) ROT+ FR (mice received Rot + FR at 20 mg/kg/day), 7) ROT+ Ex (mice received Rot + swimming Ex) and 8) ROT+ Ex + FR (mice received Rot + FR and Ex). ROT group showed significant impairment in motor performance and significant reduction in tyrosine hydroxylase (TH) density and Hsp70 expression (p< 0.05) with Lewy bodies (alpha synuclein) aggregates in corpus striatum. Also, ROT+FR, ROT+EX and ROT + Ex+ FR groups showed significant improvement in behavioral and biochemical changes, however the effect of FR alone was more potent than Ex alone (p< 0.05) and addition of Ex to FR caused no more significant improvement than FR alone. Conclusion: We concluded that, FR and Ex improved the motor performance in rotenone-induced PD rodent model which might be due to increased Hsp70 expression and TH density in corpus striatum and combination of both did not offer more protection than FR alone.