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- Volume 21, Issue 7, 2022
CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 21, Issue 7, 2022
Volume 21, Issue 7, 2022
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Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia
Diabetes mellitus is a major metabolic disorder that has now emerged as an epidemic, and it affects the brain through an array of pathways. Patients with diabetes mellitus can develop pathological changes in the brain, which eventually take the shape of mild cognitive impairment, which later progresses to Alzheimer’s disease. A number of preclinical and clinical studies have demonstrated this fact, and molecular pathways, such as amyloidogenesis, oxidative stress, inflammation, and impaired insulin signaling, are found to be identical in diabetes mellitus and dementia. However, the critical player involved in the vicious cycle of diabetes mellitus and dementia is insulin, whose signaling, when impaired in diabetes mellitus (both type 1 and 2), leads to a decline in cognition, although other pathways are also essential contributors. Moreover, it is not only the case that patients with diabetes mellitus indicate cognitive decline at a later stage, but many patients with Alzheimer’s disease also reflect symptoms of diabetes mellitus, thus creating a vicious cycle inculcating a web of complex molecular mechanisms and hence categorizing Alzheimer’s disease as ‘brain diabetes.’ Thus, it is practical to suggest that anti-diabetic drugs are beneficial in Alzheimer’s disease. However, only smaller trials have showcased positive outcomes mainly because of the late onset of therapy. Therefore, it is extremely important to develop more of such molecules that target insulin in patients with dementia along with such methods that diagnose impaired insulin signaling and the associated cognitive decline so that early therapy may be initiated and the progression of the disease can be prevented.
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Mechanisms Involved in Neuroprotective Effects of Transcranial Magnetic Stimulation
Transcranial Magnetic Stimulation (TMS) is widely used in neurophysiology to study cortical excitability. Research over the last few decades has highlighted its added value as a potential therapeutic tool in the treatment of a broad range of psychiatric disorders. More recently, a number of studies have reported beneficial and therapeutic effects for TMS in neurodegenerative conditions and strokes. Yet, despite its recognised clinical applications and considerable research using animal models, the molecular and physiological mechanisms through which TMS exerts its beneficial and therapeutic effects remain unclear. They are thought to involve biochemical-molecular events affecting membrane potential and gene expression. In this aspect, the dopaminergic system plays a special role. This is the most directly and selectively modulated neurotransmitter system, producing an increase in the flux of dopamine (DA) in various areas of the brain after the application of repetitive TMS (rTMS). Other neurotransmitters, such as glutamate and gamma-aminobutyric acid (GABA) have shown a paradoxical response to rTMS. In this way, their levels increased in the hippocampus and striatum but decreased in the hypothalamus and remained unchanged in the mesencephalon. Similarly, there are sufficient evidence that TMS up-regulates the gene expression of BDNF (one of the main brain neurotrophins). Something similar occurs with the expression of genes such as c-Fos and zif268 that encode trophic and regenerative action neuropeptides. Consequently, the application of TMS can promote the release of molecules involved in neuronal genesis and maintenance. This capacity may mean that TMS becomes a useful therapeutic resource to antagonize processes that underlie the previously mentioned neurodegenerative conditions.
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Neurodegenerative Disorders and the Current State, Pathophysiology, and Management of Parkinson’s Disease
Authors: Rahul and Yasir SiddiqueIn the last few decades, major knowledge has been gained about pathophysiological aspects and molecular pathways behind Parkinson’s Disease (PD). Based on neurotoxicological studies and postmortem investigations, there is a general concept of how environmental toxicants (neurotoxins, pesticides, insecticides) and genetic factors (genetic mutations in PD-associated proteins) cause depletion of dopamine from substantia nigra pars compacta region of the midbrain and modulate cellular processes leading to the pathogenesis of PD. α-Synuclein, a neuronal protein accumulation in oligomeric form, called protofibrils, is associated with cellular dysfunction and neuronal death, thus possibly contributing to PD propagation. With advances made in identifying loci that contribute to PD, molecular pathways involved in disease pathogenesis are now clear, and introducing therapeutic strategy at the right time may delay the progression. Biomarkers for PD have helped monitor PD progression; therefore, personalized therapeutic strategies can be facilitated. In order to further improve PD diagnostic and prognostic accuracy, independent validation of biomarkers is required.
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Tremor and Rigidity in Patients with Parkinson’s Disease: Emphasis on Epidemiology, Pathophysiology and Contributing Factors
Authors: Shivam Kumar, Lav Goyal and Shamsher SinghParkinson's disease (PD) is the second most prominent neurodegenerative movement disorder after Alzheimer’s disease, involving 2-3% of the population aged above 65 years. This is mainly triggered by the depletion of dopaminergic neurons located in substantia nigra pars compacta (SNpc) in the region of basal ganglia. At present, diagnosis for symptoms of PD is clinical, contextual, unspecified and therapeutically incomprehensive. Analysis of various causes of PD is essential for an accurate examination of the disease. Among the different causes, such as tremors and rigidity, unresponsiveness to the current treatment approach contributes to mortality. In the present review article, we describe various key factors of pathogenesis and physiology associated with tremors and rigidity necessary for the treatment of PI (postural instability) in patients with PD. Additionally, several reports showing early tremor and rigidity causes, particularly age, cortex lesions, basal ganglia lesions, genetic abnormalities, weakened reflexes, nutrition, fear of fall, and altered biomechanics, have been explored. By summarizing the factors that contribute to the disease, histopathological studies can assess rigidity and tremor in PD. With a clear understanding of the contributing factors, various prospective studies can be done to assess the incidence of rigidity and tremors.
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Strategic Approaches to Target the Enzymes using Natural Compounds for the Management of Alzheimer’s Disease: A Review
Authors: Syed S. Ahmad, Kaiser Younis, Jeandet Philippe, Michael Aschner and Haroon KhanAlzheimer's Disease (AD) is a chronic neurodegenerative disease. It is clinically characterized by memory loss and intellectual decrease, among other neurological deficits. The etiology of AD is not completely understood but includes amyloid plaques and intracellular helical filaments as well as neurofibrillary tangles with hyperphosphorylated tau protein. AD is also associated with alterations in amyloid processing genes, such as PSEN1 or PSEN2 and APP. The modulation of the immune system, cholesterol metabolism, and synaptic vesicle endocytosis have all been shown to remediate AD. In this review, enzymes such as AChE, BuChE, β-secretase, γ-secretase, MAO, and RAGE are discussed as potential targets for AD treatment. The aim of this review was to address the molecular mechanisms as well as various genetic factors in AD etiology. The use of natural compounds against these targets might be beneficial for the management of AD.
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Clinical Efficacy of Cerebrolysin and Cerebrolysin plus Nootropics in the Treatment of Patients with Acute Ischemic Stroke in Vietnam
Aims: To investigate the efficacy and safety of Cerebrolysin and Cerebrolysin plus nootropics in the routine treatment of patients with acute ischemic stroke (AIS). Background: Acute ischemic stroke (AIS) is a leading cause of disability with unmet treatment needs lacking effective drug therapy. Multimodal drugs modulating stroke pathophysiology as Cerebrolysin constitute a good therapeutic option. Objective: In this study, we assessed the effects of Cerebrolysin and Cerebrolysin plus nootropics, in comparison with other nootropic drugs alone, on functional, neurological and cognitive recovery of patients with AIS in Vietnam. Methods: This non-interventional, controlled, open-label, prospective and multicenter study included 398 AIS patients (234 males) treated with Cerebrolysin (n=190; 20 i.v. infusions of 10 ml), other nootropics (comparator group; n=86), or a combination of both (n=122). The study primary endpoint was the modified Ranking Scale (mRS) score on day 90. Secondary endpoints included study-period change in NIHSS score; percentage of well-recovered (mRS 0-2) patients, the proportion of good NIHSS response (≥6 points) cases, and MoCA scores at day 90; and safety indicators. Results: Compared with other nootropics, both Cerebrolysin and combined therapy induced significant improvements (p<0.001) in: Functional recovery (mRS scores); percentage of well-recovered patients (Cerebrolysin: 81.6%; combination: 93.4%; comparator: 43.0%); neurological recovery (study- period NIHSS change); proportion of good NIHSS responders (Cerebrolysin: 77.5%; combination: 92.5%; comparator: 47.6%); and MoCA scores (Cerebrolysin: 23.3±4.8; combination: 23.7±4.1; comparator: 15.9±7.7). Compared to Cerebrolysin, combined therapy improved (p<0.01) mRS outcomes and NIHSS change, but not MoCA scores, in moderate-severe stroke (NIHSS>11) cases only. No drug-related adverse events were reported. Conclusion: Cerebrolysin alone or combined with other nootropics was effective and safe in routine AIS treatment, during both acute and recovery phases, which supports its use in daily clinical practice. Others: According to the results of this multicenter study, the importance of reducing differences in the treatment regimens of AIS in Vietnam should be further emphasized.
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Rolipram Rescues Memory Consolidation Deficits Caused by Sleep Deprivation: Implication of the cAMP/PKA and cAMP/Epac Pathways
Authors: Ahmed Maher, Nesrine El Sayed, Heba Nafea and Mohamed GadBackground: Over the last few years, the number of people suffering from sleeping disorders has increased significantly despite negative effects on cognition and an association with brain inflammation. Objectives: We assessed memory deficits caused by Sleep Deprivation (SD) to determine the therapeutic effect of phosphodiesterase 4 (PDE4) inhibitors on SD-induced memory deficits and to investigate whether the modulation of memory deficits by PDE4 inhibitors is mediated by a protein kinase A (PKA)-independent pathway in conjunction with a PKA-dependent pathway. Methods: Adult male mice were divided into four groups. Three SD groups were deprived of Rapid Eye Movement (REM) sleep for 12 h a day for six consecutive days. They were tested daily in the Morris water maze to evaluate learning and memory. One of the SD groups was injected with a PDE4 inhibitor, rolipram (1 mg/kg ip), whereas another had rolipram co-administered with chlorogenic acid (CHA, 20 mg/kg ip), an inhibitor of PKA. After 6 days, the mice were sacrificed, and the hippocampi were evaluated for cyclic AMP (cAMP) and nuclear factor Nrf-2 levels. The hippocampal expression of PKA, phosphorylated cAMP Response Element-Binding Protein (CREB), and phosphorylated glycogen synthase 3β (Ser389) were also evaluated. Results: SD caused a significant decrease in cAMP levels in the brain and had a detrimental effect on learning and memory. The administration of rolipram or rolipram+CHA resulted in an improvement in cognitive function. Conclusion: The present study provides evidence that restoration of memory with PDE4 inhibitors occurs through a dual mechanism involving the PKA and Epac pathways.
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Volumes & issues
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Volume 23 (2024)
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Volume 22 (2023)
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Volume 21 (2022)
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Volume 20 (2021)
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Volume 19 (2020)
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Volume 18 (2019)
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Volume 17 (2018)
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Volume 16 (2017)
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Volume 15 (2016)
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Volume 14 (2015)
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Volume 13 (2014)
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Volume 12 (2013)
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Volume 11 (2012)
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Volume 10 (2011)
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Volume 9 (2010)
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Volume 8 (2009)
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Volume 7 (2008)
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Volume 6 (2007)
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Volume 5 (2006)