CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 16, Issue 6, 2017

Background: Cognitive impairment is a major manifestation of schizophrenia and a crucial treatment target as these deficits are closely related to patients' functional outcomes. Cognitive remediation is the gold-standard practice to address cognitive deficits in schizophrenia. There is clear evidence stating that cognitive remediation improves cognitive function and promotes structural neuroplastic changes in patients with schizophrenia, with brain-derived neurotrophic factor (BDNF) expression emerging as a potential biomarker for its efficacy. This is particularly important as there is clear evidence relating atypical BDNF expression to cognitive impairment in patients with schizophrenia. Despite the valuable role of cognitive remediation in the management of schizophrenia, there is still a need to develop methods that allow maximizing its efficacy. Method and Results: In this review, we present a hypothesis arguing that cognitive remediation efficacy for patients with schizophrenia can be enhanced by aerobic exercise-induced BDNF upregulation. There have been a few trials reporting that combining aerobic exercise with cognitive training was superior to cognitive training alone to improve cognitive functioning in patients with schizophrenia. Furthermore, there is preliminary evidence suggesting that combined aerobic and cognitive training can increase peripheral BDNF levels. Conclusion: Thereby, engaging in aerobic exercise in close temporal proximity to cognitive remediation may allow achieving a state of neuroplastic readiness in the brain, facilitating cognitive functioning enhancement. Although this hypothesis still lacks evidence, future clinical trials using cognitive remediation for schizophrenia should explore strategies to maximize neuroplasticity and achieve optimal cognitive improvements.

Background: Parkinson's disease (PD) is the second most common neurological disorder characterized by loss of dopaminergic fibers in the basal ganglia and presence of Lewy bodies. Method and Results: The literature suggests that caffeine plays multiple roles in PD. Epidemiological studies showed that caffeine intake was associated with less risk of developing PD, especially in genetically susceptible patients. On the level of Lewy bodies' formation, caffeine binds to α-synuclein protein inducing conformational changes and preventing their aggregation. On the level of mitochondrial stress, caffeine acts as an antioxidant that reduces oxidative stress in PD and therefore, slows the progression of the disease. On the level of dopamine release, the literature suggests that caffeine increases dopamine release and the number of dopamine receptors in the striatum via A2a receptor antagonism. Conclusion: As an adjuvant treatment, caffeine interacts with antiparkinsonian medications and can alter levodopa pharmacokinetics, reduce dyskinesia, and improve gait in patients with freezing of gait. In this review, we discussed the potential of caffeine as a possible neuroprotective agent and as an addon therapy for PD.

Background: Chronic pain is treated most commonly with opioid analgesics, anti-inflammatory steroids and nonsteroidal anti-inflammatory drugs. Method: However, these compounds are not uniformly effective and their clinical use is constrained by unwanted side effects. GABAergic neurons are located in spinal nociceptive circuits suggesting that drugs with affinity at these receptors, including benzodiazepine-like drugs, may provide an alternative to opioids for the treatment of pain. However, systemically administered conventional benzodiazepines fail to produce antihyperalgesic effects, likely due to their concurrent sedative properties. Results: Recent evidence suggests that by targeting specific benzodiazepine-sensitive GABAA receptor subtypes, the sedative properties of benzodiazepines can be circumvented and these compounds may be useful alternatives to opioids for the treatment of chronic pain. Conclusion: The present review provides an overview of the GABAA receptor subtypes involved in pain transmission as well as implications for the development of analgesic medications.

Background: Worldwide, at least 2.8 million people die each year as a result of being overweight or obese. Obesity leads to metabolic syndrome, a pathological condition characterized by adverse metabolic effects on blood pressure, cholesterol, triglycerides and insulin resistance. Population- based investigations have suggested that obesity and metabolic syndrome may be associated with poorer cognitive performance. Method: A structured search of bibliographic source (PubMed) was undertaken. The following terms “inflammation and obesity and brain”, “cholinergic system and obesity”, “cholinergic system and metabolic syndrome”, “Cognitive impairment and obesity” and “metabolic syndrome and brain” were used as search strings. Results: Over 200 papers, mainly published in the past 10 years were analysed. The major results regarded keyword “metabolic syndrome and brain” followed by, “Cognitive impairment and obesity”, “inflammation and obesity and brain”, “cholinergic system and obesity” and “cholinergic system and metabolic syndrome”. Most papers were pre-clinical but, in general, they were inhomogeneous. Therefore, the results were cited according their contribution to clarify the molecular involvement of obesity and/or metabolic syndrome in cholinergic impairment. Conclusion: This review focuses on the correlation between brain cholinergic system alterations and high-fat diet, describing the involvement of cholinergic system in inflammatory processes related to metabolic syndrome and obesity, which may lead to cognitive decline. Metabolic syndrome has been suggested as a risk factor for cerebrovascular diseases and has been associated with cognitive impairment in different functional brain domains. Preclinical and clinical studies have identified the cholinergic system as a specific target of metabolic syndrome and obesity. The modifications of cholinergic neurotransmission and its involvement in neuro-inflammation may be related to cognitive impairment that affects obese patients.

Background: A considerable amount of data suggests the age-related impairments of mitochondrial functions in the development of sporadic forms of neurodegenerative pathologies. Mitochondria and the phenomenon of mitochondrial permeability transition (MPT), which marks the point of no return in cell death cascades, have special value in this regard. It is important that the vulnerability to MPT-inducing factors is increased with aging. Simultaneously, a decrease in the calcium retention capacity of mitochondria is developed, which leads to the disturbance of the functional activity of neurons. Method: The systematic investigations and web content related to the importance of MPT as the target for the search of neuroprotective and cognitive enhancing drugs, especially with multitargeted action, are reviewed. Results: Here, we have highlighted some experimental data that determines the importance of mitochondria for the search of neuroprotective drugs, and drugs with multitargeted action. We have also discussed a number of new compounds with similar properties. Being MPT inhibitors/modulators, virtually all the compounds described in this review have the ability to exhibit a neuroprotective effect, interact with some other targets, providing coupled beneficial therapeutic effects such as cognitive stimulation, anti-seizure, and antidepressant actions. Conclusion: Inhibitors of MPT, which increases calcium retention capacity of mitochondria, are considered as promising neuroprotective drugs able not only to halt the neurodegenerative cascade, but also to increase the functional activity of neurons.

Background: Status epilepticus (SE), is characterized by high mortality and morbidity, which can cause neuronal injury, neuronal death and alteration of neuronal networks, Recently, inflammation was shown to play a significant role in SE pathogenesis. And miRNA-146a has been shown to be involved in inflammation and to inhibit inflammatory cytokines through NF-ΚB pathway. In our study, we investigated the relationship between inflammation and miR-146a expression. Method: The SE rat model was induced by lithium-pilocarpine. Hematoxylin and eosin staining (H) was performed to observe the histopathology of the rat hippocampus. The expression of COX-2, TNF-α, IL-6 and IL-1β were respectively measured by Western blot and Bio-Plex ProTM Assays. The miR-146a expression in hippocampus tissue was measured by Quantitative real-time PCR. Results: microRNA-146a was highly expressed in the hippocampus of SE rats coupled with increased level of inflammatory cytokines than the normal group. And TQ can attune the expression of inflammatory cytokines, meanwhile, miR-146a was lower in TQ group. The expression of miRNA-146a were positively correlated with the level of inflammatory reaction. Conclusion: TQ may alleviate the inflammatory reaction by inhibiting the NF-ΚB signaling pathway. Our study shows that miRNA-146a was involved in the inflammatory response and indicated inflammation severity in SE rats. Therefore, miRNA-146a may serve as a potential biomarker or a therapeutic target in SE.

Background: Epilepsy is a central disorder associated with neuronal damage and brain hypometabolism. It has been reported that antidepressant drugs show anticonvulsant and neuroprotective effects in different animal models of seizures and epilepsy. Aims: The purpose of this study was to investigate the eventual short-term brain impairment induced by a single low convulsant dose of the potassium channel blocker 4-aminopyridine (4-AP) and the eventual neuroprotective effects exerted by fluoxetine, a prototypical selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). Method: In vivo 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) and several histological assessments were carried out in adult male rats after i.p. administration of 3 mg/kg 4-AP for evaluating eventual brain metabolism impairment and signs of hippocampal damage. We also evaluated the effects of a short-term fluoxetine treatment (10 mg/kg, i.p. for 7 days) in this seizure model. Results: [18F]FDG PET analysis revealed no changes in the regional brain metabolism on day 3 after 4-AP injection. The histological assessments revealed signs of damage in the hippocampus, a brain area usually affected by seizures. Thus, reactive gliosis and a significant increase in the expression of caspase-9 were found in the aforementioned brain area. By contrast, we observed no signs of neurodegeneration or neuronal death. Regarding the effects of fluoxetine, this SSRI showed beneficial neurologic effects, since it significantly increased the seizure latency time and reduced the abovementioned 4-AP-induced hippocampal damage markers. Conclusion: Overall, our results point to SSRIs and eventually endogenous 5-HT as neuroprotective agents against convulsant-induced hippocampal damage.

Background: Parkinson's disease (PD) is the subject of intense efforts to develop strategies that slow down or stop disease progression and disability. Substantial evidence points to a prominent role for neuroinflammation in the underlying dopaminergic cell death. Ultramicronized palmitoylethanolamide (um-PEA) is well-known for its ability to promote the resolution of neuroinflammation and exert neuroprotection. This study was designed to assess the efficacy of um-PEA as adjuvant therapy in patients with advanced PD. Method: Thirty PD patients receiving levodopa were included in the study. The revised- Movement Disorder Society/Unified Parkinson's Disease Rating Scale (MDS-UPDRS) questionnaire was used to assess motor and non-motor symptoms. Clinical assessments were carried out before and after addition of um-PEA (600 mg). MDS-UPDRS questionnaire total score for parts I, II, III, and IV was analyzed using the Generalized Linear Mixed Model, followed by the Wilcoxon signed-rank test to evaluate the difference of each item's mean score between baseline and end of um-PEA treatment. Results: Addition of um-PEA to PD patients receiving levodopa therapy elicited a significant and progressive reduction in the total MDS-UPDRS score (parts I, II, III and IV). For each item, the mean score difference between baseline and end of um-PEA treatment showed a significant reduction in most nonmotor and motor symptoms. The number of patients with symptoms at basal was reduced after one year of um-PEA treatment. None of the participants reported side effects attributable to the addition of um-PEA. Conclusion: um-PEA slowed down disease progression and disability in PD patients, suggesting that um-PEA may be an efficacious adjuvant therapy for PD.

Background: In April 2015, the US Food and Drug Administration approved the first generic glatiramer acetate, Glatopa® (M356), as fully substitutable for Copaxone® 20 mg/mL for relapsing forms of multiple sclerosis (MS). This approval was accomplished through an Abbreviated New Drug Application that demonstrated equivalence to Copaxone. Method: This article will provide an overview of the methods used to establish the biological and immunological equivalence of the two glatiramer acetate products, including methods evaluating antigenpresenting cell (APC) biology, T-cell biology, and other immunomodulatory effects. Results: In vitro and in vivo experiments from multiple redundant orthogonal assays within four biological processes (aggregate biology, APC biology, T-cell biology, and B-cell biology) modulated by glatiramer acetate in MS established the biological and immunological equivalence of Glatopa and Copaxone and are described. The following were observed when comparing Glatopa and Copaxone in these experiments: equivalent delays in symptom onset and reductions in “disease” intensity in experimental autoimmune encephalomyelitis; equivalent dose-dependent increases in Glatopa- and Copaxone- induced monokine-induced interferon-gamma release from THP-1 cells; a shift to a T helper 2 phenotype resulting in the secretion of interleukin (IL)-4 and downregulation of IL-17 release; no differences in immunogenicity and the presence of equivalent “immunofingerprints” between both versions of glatiramer acetate; and no stimulation of histamine release with either glatiramer acetate in basophilic leukemia 2H3 cell lines. Conclusion: In summary, this comprehensive approach across different biological and immunological pathways modulated by glatiramer acetate consistently supported the biological and immunological equivalence of Glatopa and Copaxone.

Background: Pyrroloquinoline quinone is an anionic, water-soluble compound with antioxidant characteristic. The role of pyrroloquinoline quinone in pharmacology and nutrition has attracted wide attention of researchers. Although a few experiments have confirmed that pyrroloquinoline quinone plays an obvious effective role in neuroprotection. There are few reports about the effect of pyrroloquinoline quinone on traumatic brain injury. Traumatic brain injury is one of the leading causes for adult disability and death. So far, there are no effective treatment methods for the injury because of its complex pathophysiology. Method: In the present study, a model of traumatic brain injury in rat was established to study the role of pyrroloquinoline quinone in central nervous system injury. Results: The results showed that the protein expression of cleaved-Caspase 3/Caspase 3 increased after traumatic brain injury and the expression decreased by treatment with 2mM pyrroloquinoline quinone. Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) staining displayed that the TUNEL positive signals were up-regulated after traumatic brain injury and were down-regulated after treatment with 2mM pyrroloquinoline quinone. The protein expression of LC3II/LC3I or lysosome-associated membrane protein 2(LAMP2) was elevated after traumatic brain injury and reduced after administration with 2mM pyrroloquinoline quinone. Transmission electron microscopy showed that the number of autophagosomes increased markedly after traumatic brain injury and decreased on administration of 2mM pyrroloquinoline quinone. Electroencephalogram indicated that pyrroloquinoline quinone improved brain electrophysiological function after traumatic brain injury. The results of CCK-8 test showed that pyrroloquinoline quinone could increase the viability of primary astrocyte treated with Glutamate. Lactate dehydrogenase (LDH) assay demonstrated that pyrroloquinoline quinone decreased LDH content in primary astrocyte exposed to Glutamate. Conclusion: Pyrroloquinoline quinone could play a neuroprotective role after traumatic brain injury in rat, which might be associated with inhibiting apoptosis and autophagy caused by traumatic brain injury.