CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 17, Issue 10, 2018

Background & Objective: Cariprazine is a piprazine derivative approved by the FDA in 2015 for the treatment of schizophrenia and bipolar manic or mixed episodes in adults. High affinity for D3 dopamine receptors and observed actions on 5HT1A, 5HT2A and alpha 1B receptors differentiate it pharmacologically from other antipsychotics. This review is a comprehensive and thorough summary of the most important findings on cariprazine use in bipolar mania and depression. Pharmacokinetics, pharmacogenetics, tolerability and safety adverse effects are discussed in this paper. Results & Conclusion: Moreover, the results from pivotal clinical trials are presented. Cariprazine represents an additional option for clinicians to treat patients with bipolar disorder. It shows a unique pharmacological profile and has demonstrated in randomized clinical trials efficacy and general tolerability compared to placebo in bipolar mania and seem to be a promising therapeutic option for bipolar depression.

Background & Objective: Epilepsy is a common and serious chronic neurological disorder that is mainly treated with antiepileptic drugs. Although current antiepileptic drugs used in clinical practice have advanced to the third generation, approximately one-third of patients are refractory to these treatments. More efficacious treatments for refractory epilepsy are therefore needed. A better understanding of the mechanism underlying refractory epilepsy is likely to facilitate the development of a more effective therapy. The abnormal expression and/or dysfunction of efflux transporters, particularly ABC transporters, might contribute to certain cases of refractory epilepsy. Inflammation in the brain has recently been shown to regulate the expression and/or function of ABC transporters in the cerebral vascular endothelial cells and glia of the blood-brain barrier by activating intracellular signalling pathways. Conclusion: Therefore, in this review, we will briefly summarize recent research advances regarding the possible role of neuroinflammation in regulating ABC transporter expression in epilepsy.

Background & Objective: Heat Shock Proteins (HSPs) increase response to many stresses in cells. Stroke is a neural shock that leads to the destruction of a large number of brain cells, whereas induction and expression of HSPs can decrease the amount of damage, and in some conditions can cure damaged cells. HSP70 family is considered as the most important member of HSPs in normal and stress condition of cells. They are strongly up-regulated by stresses and have protective roles in under stressed cells. Therefore, in this review, we briefly consider the association between HSP70 and stroke. We searched in Pubmed and Scopus databases using the specified keywords and selected the articles based on the certain association between HSP70 and stroke. HSP70 protects cells from damage through a variety of cellular and biochemical processes such as chaperone function, anti-apoptotic, anti-necrotic and anti-inflammatory mechanisms. Conclusion: Protective effects of HSP70 in neurodegenerative shocks are illustrated in the review, and it can be concluded that the induction of HSP70 in stresses can be considered as a therapeutic factor, although it needs further studies.

Background & Objective: Regulation of composition, volume and turnover of fluids surrounding the brain and damp cells is vital. These fluids transport all substances required for cells and remove the unwanted materials. This regulation tends to act as barrier to prevent free exchange of materials between the brain and blood. There are specific mechanisms concerned with fluid secretion of the controlled composition of the brain, and others responsible for reabsorption eventually to blood and the extracellular fluid whatever their composition is. The current view assumes that choroidal plexuses secrete the major part of Cerebrospinal Fluid (CSF), while the Blood-Brain Barrier (BBB) has a much less contribution to fluid production, generating Interstitial Fluid (ISF) that drains to CSF. The skull is a rigid box; thereby the sum of volumes occupied by the parenchyma with its ISF, related connective tissue, the vasculature, the meninges and the CSF must be relatively constant according to the Monroe-Kellie dogma. This constitutes a formidable challenge that normal organisms surpass daily. The ISF and CSF provide water and solutes influx and efflux from cells to these targeted fluids in a quite precise way. Microvessels within the parenchyma are sufficiently close to every cell where diffusion areas for solutes are tiny. Despite this, CSF and ISF exhibit very similar compositions, but differ significantly from blood plasma. Many hydrophilic substances are effectively prevented from the entry into the brain via blood, while others like neurotransmitters are extremely hindered from getting out of the brain. Anatomical principle of the barrier and routes of fluid transfer cannot explain the extraordinary accuracy of fluids and substances needed to enter or leave the brain firmly. There is one aspect that has not been deeply analyzed, despite being prevalent in all the above processes, it is considered a part of the CSF and ISF dynamics. This aspect is the energy necessary to propel them properly in time, form, space, quantity and temporality. Conclusion: The recent hypothesis based on glucose and ATP as sources of energy presents numerous contradictions and controversies. The discovery of the unsuspected intrinsic ability of melanin to dissociate and reform water molecules, similar to the role of chlorophyll in plants, was confirmed in the study of ISF and CSF biology.

Background & Objective: Parkinson's disease is the second most common neurodegenerative disorder affecting more than 1% of the population averaged 60 years of age. The majority of PD cases are sporadic and are probably caused by a combination of risk factors but 5-10% of the PD cases are familial. Due to the high degree of the gene, conservation in humans, mice and insects using an animal model system is a valuable approach to further elucidate the roles of the genes in PD. Conclusion: The present review highlights the models used to study PD symptoms with special emphasis on Drosophila.

Objective: To investigate the efficacy of curcumin oral supplementation (600 mg/day, Brainoil), a natural antioxidant compound, in Amyotrophic Lateral Sclerosis (ALS). Methods: Patients were randomized into two groups: Group A received placebo for 3 months, then Brainoil for the following 3 months, Group B took Brainoil for 6 months. The evaluations were conducted at basal (T0), after 3 months of double blinded Brainoil or placebo treatment (T1), and after the 3 month open-label phase (T2). Clinical evaluations and oxidative stress biomarkers, including oxidative protein products (AOPPs), ferric reducing ability (FRAP), total thiols (T-SH) and lactate, were evaluated, compared to a control group, during an incremental forearm exercise test. Results: Over the entire study Group B showed a stable score of the ALS-FRS-r which decreased in Group A (p<0.01), in parallel with a reduction of AOPPs (p<0.01) which was not detected into Group A. Also FRAP exercise values remained stable in Group B, while in Group A they were reduced without treatment at T1 (0.05T0 exercise lactate was lower compared to Group A (p<0.01). Compared to controls, the whole ALS population showed a greater oxidative stress (p<0.001), those treated with curcumin (Group B) exhibiting decreased exercise AOPPs at T2 with values approaching those of controls. Conclusion: Although further studies are needed to confirm these data, treatment with curcumin shows encouraging results indicating a slight slowdown in disease progression, improving aerobic metabolism and oxidative damage, this also contributing to deepen knowledge into the pathogenic mechanisms of ALS.

Introduction: We evaluated the peripheral immune panel of Multiple Sclerosis (MS) patients treated for more than 10 years with interferon-beta1b (IFNβ-1b) and aimed to identify possible biomarkers of treatment response. Material and Methods: Serum samples from 70 MS patients treated with IFNβ-1b more than a decade were analysed for 15 cytokines, that were correlated with the disability score, annual relapse ratio (ARR): the total number of relapses-ARR_0, relapse on treatment-ARR_1 and demographic data. Two groups were defined based on the levels of disability, calculated using the Expanded Disability Status Scale (EDSS): G1 – recurrent-remissive and G2 – secondary-progressive. Furthermore, we split the patients based on gender (G1_f, G1_m, G2_f, G2_m). Results: The ARR was reduced after treatment was instituted. We found positive correlations between IL_25 and EDSS in G1_f and G2_f, tumor necrosis factor α (TNFα) and ARR_1 and ARR_0 in G1, and IL_17F with ARR_1. Negative correlations were for IL_25 and ARR_0 and ARR_1. SCD40L intensely positively correlated with IL_31 in G1 and G2. Conclusion: After more than a decade of treatment, IFNβ-1b offers good results by reducing relapses and slowing disability progression. Several biomarkers can be used to assess the patient's response. High levels of IL_17 and TNFα will indicate a more active form of the disease. IL-25 may exert a positive influence in male MS patients and should be considered for future studies, together with the co-modulation between sCD40L and IL_31. Our method allowed us to screen the peripheral immune panel and can be used for assessing the peripheral levels of the above-mentioned cytokines.