CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 23, Issue 2, 2024

Stroke is a multifactorial vascular disease and remains a leading cause of disability in the United States. Strokes can be ischemic or hemorrhagic in nature and secondary to arterial or venous disease, making determining the etiology and secondary prevention strategy important for preservation of the injured brain, prevention of recurrent strokes, and in the maintenance of good functional outcomes for patients impacted by stroke. In this narrative review, we provide a synopsis of the available medical evidence surround selection, timing, and choice of therapy, including utilization of left atrial appendage closure, in patients with ischemic, hemorrhagic or venous stroke.

Protein misfolding and aggregation is the phenomenon of the generic propensity of proteins, considered as a dark side of the protein world, and its exact mechanism is still not deciphered. Understanding the complexity of protein aggregation is currently the primary apprehension and challenge in biology and medicine due to their association with various debilitating human proteinopathies and neurodegenerative diseases. The mechanism of protein aggregation, associated diseases, and the development of efficient therapeutic strategies against these diseases are very challenging. These diseases are caused by different proteins, each protein with different mechanisms and consisting of various microscopic phases or events. These microscopic steps are functioning on different timescales during aggregation. Here, we highlighted the different features and current trends in protein aggregation. The study thoroughly recapitulates the various factors influencing, possible causes, types of aggregates and aggregation, their different proposed mechanisms, and the methods used to study the aggregation. Additionally, the formation and elimination of misfolded or aggregated proteins in the cell, the role of the ruggedness of the protein folding landscape in protein aggregation, proteinopathies, and the challenges for their prevention are comprehensively elucidated. A holistic understanding of different aspects of aggregation, molecular steps governing the various features of protein quality control, and crucial queries about the modulation of these processes and their interactions with other systems in cellular protein quality control can be considered conducive to comprehending the mechanism, designing effective approaches towards prevention of protein aggregation, rationalizing the etiology and development of novel strategies against therapy and management of the proteinopathies.

Background: Animal models for drug discovery and development in Parkinson ’s disease have played an important role in the characterization of the pathophysiology of diseases and associated mechanisms of injury, drug target identification, and evaluation of novel therapeutic agents for toxicity/ safety, pharmacokinetics, pharmacodynamics, and efficacy. Objective: The review is intended to reform the scope, advantages, and limitations of various Parkinson’s Disease models and their scope in translational research. The lack of a gold standard for PD animal models presents a major challenge in devising a validation system. This review is an attempt to provide a way to adopt the validation approach for PD animal model for research. Methods: Because underlying disease mechanisms are so similar across species, it is possible to extrapolate results from Parkinson's disease studies using animal models. Furthermore, behavioural tests used to access the neurobehavioral test with its limitations were explored for rodents, non-human primates, lower-order animals, and invertebrates. The role of gender selectivity and non-selectivity is the one major concern in PD model validation that is addressed in the review. Results: The rigorous validation has been done on animal models for Parkinson's disease (PD) based on comparisons to the human state. Regarding toxicological and safety investigations in PD, non-animal options must be thoroughly validated. There are both advantages and disadvantages to using animal models of Parkinson's disease as proof-of-concept research. Conclusion: The specific animal model selected for a given drug to be tested and developed depends on the goal of the specific study.

Bell palsy is a non-progressive neurological condition characterized by the acute onset of ipsilateral seventh cranial nerve paralysis. People who suffer from this type of facial paralysis develop a droop on one side of their face, or sometimes both. This condition is distinguished by a sudden onset of facial paralysis accompanied by clinical features such as mild fever, postauricular pain, dysgeusia, hyperacusis, facial changes, and drooling or dry eyes. Epidemiological evidence suggests that 15 to 23 people per 100,000 are affected each year, with a recurrence rate of 12%. It could be caused by ischaemic compression of the seventh cranial nerve, which could be caused by viral inflammation. Pregnant women, people with diabetes, and people with respiratory infections are more likely to have facial paralysis than the general population. Immune, viral, and ischemic pathways are all thought to play a role in the development of Bell paralysis, but the exact cause is unknown. However, there is evidence that Bell's hereditary proclivity to cause paralysis is a public health issue that has a greater impact on patients and their families. Delay or untreated Bell paralysis may contribute to an increased risk of facial impairment, as well as a negative impact on the patient's quality of life. For management, antiviral agents such as acyclovir and valacyclovir, and steroid treatment are recommended. Thus, early diagnosis accompanied by treatment of the uncertain etiology of the disorder is crucial. This paper reviews mechanistic approaches, and emerging medical perspectives on recent developments that encounter Bell palsy disorder.

Traumatic brain injury (TBI) is a major source of death and disability worldwide; however, its pathogenesis is no longer regarded as an immediate, irreversible process that occurs at the time of injury. Long-term alterations in personality, sensory-motor function, and cognition are common among trauma survivors. The pathophysiology of brain injury is very complex, so it is difficult to understand. Establishing models such as weight drop, controlled cortical impact, fluid percussion, Accelerationdeceleration, hydrodynamic and cell line culture, etc., to simulate the event within controlled conditions has been a critical step in better understanding traumatic brain injury and enabling improved therapy. Establishing effective in vivo and in vitro models of traumatic brain injury and mathematical models is described here as part of the discovery of neuroprotective techniques. Some models, such as weight drop, fluid percussion, and cortical impact, help us understand the pathology of brain injury and provide suitable and effective therapeutic doses of the drug. A chemical mechanism such as prolonged or toxic exposure to chemicals and gases causes toxic encephalopathy, an acquired brain injury that may or may not be reversible. This review provides a comprehensive overview of numerous in-vivo and in-vitro models and molecular pathways to advance the knowledge of TBI. It covers traumatic brain damage pathophysiology, including apoptosis, the function of chemicals and genes, and a brief discussion on putative pharmacological remedies.

In the central nervous system (CNS), G-protein-coupled receptors (GPCRs) are the most common targets of neuropharmacological drugs. GPCRs are activated by various neurotransmitters, which results in slow synaptic transmission. Recently, remarkable progress has been achieved in identifying genes and signaling pathways linked to the risk of psychiatric disorders. Even though the biological mechanisms governing psychiatric disorders, such as mood disorders and schizophrenia, are uncertain, GPCRs are essential in diagnosing and treating various ailments. However, due to the complicated reasons responsible for these disorders, there has been a significant decrease in the pipeline for the progression of novel psychiatric medications throughout the world. Antipsychotics and antidepressants target GPCRs, which regulate various subsequent signaling pathways and play a key role in altering brain function. The advancement of our knowledge of GPCR signaling has opened up new avenues for developing customized medications. This review summarizes the current understanding of therapeutic GPCR targets for psychiatric disorders. For patients resistant to current therapies, the future development of new drugs targeting GPCR signaling pathways is promising.

Background: Plants and their extracts like ginger, garlic, Curcuma, Salvia, and Ginkgo are best known for their anti-oxidative and anti-inflammatory responses. These plants have shown their anti-Alzheimer’s properties in various in vivo and in vitro studies. Their diverse phytochemicals play a protective role against amyloid-beta-induced neurotoxicity and improve cognitive and learning impairments. These plants have a wide range of bioactive compounds, including alkaloids, flavonoids, phenols, glycosides, terpenoids, coumarins, and saponins. These chemicals scavenge the free radicals, lower the amyloid burden, improve memory dysfunction, and inhibit acetylcholinesterase activity. Some of the clinical trials and animal-based studies suggested the protective role of these plants and their extract mentioned in the literature. Methods: The articles for this review were majorly searched from popular search engines, viz, Google Scholar, PubMed, and Scopus. Results: Medicinal plants improve cognitive and memory impairments by inhibiting acetylcholinesterase activity and scavenging free oxygen species by activating superoxide dismutase, catalase, and GSH activity. The plant extracts reduce amyloid insult by inactivating the beta-site amyloid precursor protein cleaving enzyme (BACE). The inactivation of Caspase 3 and 9 reduces apoptosis. Furthermore, the stimulation of microglial cells and astrocyte reduce inflammation by lowering chemokines and interleukins. Discussion: The medicinal plants help to reduce AD pathogenesis by controlling different pathways and could be used as a therapeutic agent against the symptoms.

Background: Different studies have been conducted to understand how patients with unipolar and bipolar depression differ in terms of cognitive and affective symptoms as well as in psychosocial function. Furthermore, the impact of antidepressants, second-generation antipsychotics, and mood stabilizers on these dimensions needs to be characterized, as well as the best psychometric approach to measure changes after pharmacological treatment. Objectives: This study aims to analyze the impact of psychotropic drugs on cognitive, affective, and psychosocial functioning in MDD and BD patients; to test the sensitivity of psychometric tools for measuring those changes; also, to understand how psychosocial abilities are associated with affective and cognitive dimensions in patients with MDD and BD. Methods: A total of 22 patients with MDD and 21 patients with BD in the depressive phase were recruited. Several psychometric tests were administered to assess affective, cognitive, and psychosocial symptoms before and after 12 weeks of drug treatment (T0 and T1) with different psychotropic drugs including second-generation antidepressants, second-generation antipsychotics and mood stabilizers (lamotrigine). Results: MDD patients showed significant improvement in MoCA, Delayed Recall of Rey’s 15 Words and HDRS, while a significant worsening was detected on Digit Span Backwards and on FAST scores. Instead, patients with BD showed significant improvements in the MoCA as the MDD patients, but only a trend of improvement (non-statistically significant) on the BDI-II. A positive correlation was detected in both groups between FAST and HDRS and BDI-II scores, especially in BD patients. Conclusion: Our results demonstrate that drug treatment with psychotropic drugs can improve cognitive and affective symptoms, but not all psychometric tools may be equally sensitive to detect those changes in MDD vs. BD patients. Moreover, we found that affective and cognitive dimensions can be considered as different psychopathological dimensions both in unipolar and bipolar depression.