CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 20, Issue 9, 2021

Alzheimer’s Disease (AD) is characterized by progressive memory loss due to neurodegeneration that occurs mainly during aging. The accumulation of senescent cells has been related to aging. Furthermore, the expression of the variant ApoE ε4 is a critical risk factor for AD. Some events that occur in senescence, such as the secretion of pro-inflammatory molecules, and metabolic and epigenetic changes, in addition to the detection of ApoE4, may accelerate the progression of AD. Here, we discuss the implications of cellular senescence and the ApoE variants in AD. Molecular studies of these risk factors for AD may hence be pivotal to define new biomarkers and novel therapeutic strategies for this neurodegenerative pathology.

AMP-activated protein kinase (AMPK) is a serine/threonine kinase and a driving or deterrent factor in the development of neurodegenerative diseases and dementia. AMPK affects intracellular proteins like the mammalian target of rapamycin (mTOR) Peroxisome proliferator-activated receptor-γ coactivator 1-α (among others) contributes to a wide range of intracellular activities based on its downstream molecules such as energy balancing (ATP synthesis), extracellular inflammation, cell growth, and neuronal cell death (such as apoptosis, necrosis, and necroptosis). Several studies have looked at the dual role of AMPK in neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington disease (HD) but the exact effect of this enzyme on dementia, stroke, and motor neuron dysfunction disorders has not been elucidated yet. In this article, we review current research on the effects of AMPK on the brain to give an overview of the relationship. More specifically, we review the neuroprotective or neurodegenerative effects of AMPK or AMPK activators like metformin, resveratrol, and 5-aminoimidazole-4-carboxamide- 1-β-d-ribofuranoside on neurological diseases and dementia, which exert through the intracellular molecules involved in neuronal survival or death.

Parkinson’s disease is a common neurodegenerative disease affecting the movement and well-being of most elderly. The manifestations of Parkinson’s disease often include resting tremor, stiffness, bradykinesia, and muscular rigidity. The typical hallmark of Parkinson’s disease is the destruction of neurons in the substantia nigra and the presence of Lewy bodies in different compartments of the central nervous system. Due to various limitations to the currently available treatments, immunotherapies have emerged to be the new approach to Parkinson’s disease treatment. This approach shows some positive outcomes on the efficacy by removing the aggregated species of alpha-synuclein, which is believed to be one of the causes of Parkinson’s disease. In this review, an overview of how alpha-synuclein contributes to Parkinson’s disease and the effects of a few new immunotherapeutic treatments, including BIIB054 (cinpanemab), MEDI1341, AFFITOPE, and PRX002 (prasinezumab) that are currently under clinical development, will be discussed.

Elevated peripheral expression of homocysteine (Hcy) is associated with an increased risk of coronary heart disease and stroke, diabetes, and cancer. It is also associated with cognitive impairment as it has been reported that high levels of Hcy cause cognitive dysfunction and memory deficit. Among several etiological factors that contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Hcy seems to directly contribute to the generation of neurotoxicity factors. This study aims to hypothesize the molecular mechanism by which exercise can reduce the risk of neurological complications promoted by hyperhomocysteinemia (HHcy), and discuss how exercise could reduce the risk of developing AD by using bioinformatics network models. According to the genes network, there are connections between proteins and amino acids associated with Hcy, exercise, and AD. Studies have evidenced that exercise may be one of several processes by which acid nitric availability can be maximized in the human body, which is particularly important in reducing cell loss and tau pathology and, thereby, leading to a reduced risk of complications associated with HHcy and AD.

Selective GluN2B/N-methyl-D-aspartate receptor (NMDAR) antagonists have exposed their clinical effectiveness in a cluster of neurodegenerative diseases, such as epilepsy, Alzheimer’s disease, Parkinson’s disease, pain, and depression. Hence, GluN2B/NMDARs are considered to be a prospective target for the management of neurodegenerative diseases. Here, we have discussed the current results and significance of subunit selective GluN2B/NMDAR antagonists to pave the way for the establishment of new, safe, and economical drug candidates in the near future. By using summarized data of selective GluN2B/NMDAR antagonists, medicinal chemists are certainly a step closer to the goal of improving the therapeutic and side effect profile of selective antagonists. Outlined summary of designing strategies, synthetic schemes, and pharmacological evaluation studies reinvigorate efforts to identify, modify, and synthesize novel GluN2B/NMDAR antagonists for treating neurodegenerative diseases.

Background and Objective: Many studies have evaluated the risk of migraine headache in obese persons, suggesting controversial conclusions. The aim of this systematic review and meta- analysis of the observational studies was to clarify the association between migraine and obesity. Methods: Scopus and PubMed electronic databases were systematically searched up to February 2019 for observational studies providing data dealing with migraine disorder in obese subjects, as well as normal-weight controls. The random effects model was applied for assessing pool effect size, and inter-study heterogeneity was evaluated by conducting subgroup analyses. Results: Among 1122 publications, 16 studies (10 cross-sectional, 5 cohort studies and 1 case-control study) were detected and were included in the meta-analysis. The pooled data analysis illustrated an elevated risk of migraine headache (Prevalence ratio estimate = 1.29, 95% CI, 1.15 - 1.44, p = 0.000) in obese individuals compared to normal-weight persons. Subgroup analyses revealed that geographical distribution was an important source of heterogeneity (p = 0.04). Significantly greater migraine prevalence was found in European and Asian patients, but no statistically significant relationship with obesity was observed in American patients. Conclusion: Based on a cumulative meta-analysis of available studies indicating an association between migraine and obesity, obesity can be appropriately considered as an overall risk factor for migraine headaches. Additional high-quality original studies considering frequency, severity, and duration of headaches are required to clarify confident evidence.

Aim: Poor nutritional effect of junk food induces injuries to the liver and the brain but still most of the developing nations survive on these diets to compensate for the fast-paced lifestyle. The aim of the study is to infer the protein-connections behind the liver-brain axis and identify the role of these proteins in causing neurodegenerative disorders. Background: Chronic consumption of fructose and fat-rich food works as a toxin in the body and has the ability to cause a negative metabolic shift. Recently a study was published in Annals of Internal Medicine (2019) citing the loss of vision and hearing in a 14-year-old boy whose diet was strictly restricted to fries and junk-food for almost a decade. This puts the entire body on insulin resistance and related co-morbidities and causes simultaneous damaging effects on the liver as well as the brain. This work provides insights into the liver-brain axis and explains how the liver is involved in brain related disorders. Objective: In this study, transcriptomic data related to chronic eating of junk-food was analyzed and simultaneous damage that happens in the liver and the brain was assessed at the molecular level. Methods: Transcriptomic study was taken from the GEO database and analysed to find out the genes dysregulated in both the liver and the brain during this metabolic stress. Cytoscapev3.7 was used to decipher the signalling between the liver and the brain. This connection between both is called as the liver-brain axis. Result: The results obtained from our study indicate the role of TUBB5-HYOU1-SDF2L1-DECR1- CDH1-EGFR-SKP2-SOD1-IRAK1-FOXO1 gene signature in the decline of concurrent liver and brain health. Dysregulated levels of these genes are linked to molecular processes like cellular senescence, hypoxia, glutathione synthesis, amino acid modification, increased nitrogen content, synthesis of BCAAs, cholesterol biosynthesis, steroid hormone signalling and VEGF pathway. Conclusion: We strongly advocate that prolonged consumption of junk food is a major culprit in brain related disorders like Alzheimer’s disease and propose that receptors for brain diseases lie outside the brain and aiming them for drug discovery and design may be beneficial in future clinical studies. This study also discusses the connection between NAFLD (non-alcoholic fatty liver disease) and sAD (sporadic Alzheimer’s disease) owing to liver-brain axis.