CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 22, Issue 9, 2023

In the last two decades the validity of clinical trials in psychiatry has been subjected to discussion. The most accepted clinical study method in the medical area, i.e. the randomized controlled trial (RCT), faces significant problems when applied to the psychiatric field. One of the causes for this scenario is the strict participant inclusion and exclusion criteria that may not represent the real world. The inconsistency of the different endpoint parameters that are used in the field is another cause. We think that psychiatric RCTs’ challenges, together with the underlying complexity of psychiatry, lead to a problematic clinical practice. Psychoactive substances are currently routinely tested outside of a formal clinical trial environment. Off-label psychoactive drugs are commonly prescribed, and other substances, such as herbal remedies, are also regularly consumed. These real-life experiments can teach us useful lessons. Real-world data (RWD) includes information about heterogeneous patient populations, and it can be measured with standardized parameters. Collecting RWD can also address the need for systematically documenting and sharing case reports’ outcomes. We suggest using digital tools to capture objective and continuous behavioral data from patients passively. New conclusions will be constantly drawn, possibly allowing more personalized treatment outcomes. The relevant nextgeneration decision support tools are already available.

Background: The field of medicine and synthetic drug development have advanced rapidly over the past few decades. However, research on alternative medicine, such as phytochemicals cannot be ignored. The main reason for prominent curiosity about phytochemicals stems from the belief that the usage of natural compounds are safer and have lesser detrimental side effects. Objective: The aim of the present review was to discuss in detail several phytochemicals that have been studied or are being studied in the context of various neurological disorders, including depression, Alzheimer’s disease, Huntington’s disease and even neuroinflammatory disorders, such as encephalitis. Methods: The potential roles of phytochemicals in treating or managing symptoms associated with neurological disorders have been included in this article. All data included in this paper have been pooled from various databases, including Google Scholar, PubMed, Science Direct, Springer, and Wiley Online Library. Results: Phytochemicals have been widely studied for their therapeutic properties associated with neurological disorders. Using various experimental techniques for both in vivo and in vitro experiments, studies have shown that phytochemicals do have antioxidant, anti-inflammatory and neuroprotective activities, which play major roles in the treatment of neurological diseases. Conclusion: Even though there has been compelling evidence of the therapeutic role of phytochemicals, further research is still required to evaluate the safety and efficacy of these medicines. Using previously published papers as the foundation for additional research, such as preclinical studies and clinical trials, phytochemicals can become a safer alternative to synthetic drugs for treating a spectrum of neurological diseases.

Dementia is a global health concern owing to its complexity, which also poses a great challenge to pharmaceutical scientists and neuroscientists. The global prevalence of dementia is approximately 47 million, which may increase by three times by 2050. Alzheimer’s disease (AD) is the most common cause of dementia. AD is a severe age-related neurodegenerative disorder characterized by short-term memory loss, aphasia, mood imbalance, and executive function. The etiology of AD is still unknown, and the exact origin of the disease is still under investigation. Aggregation of amyloid β (Aβ) plaques or neurotoxic Aβo oligomers outside the neuron is the most common cause of AD development. Amyloid precursor protein (APP) processing by β secretase and γ secretase produces abnormal Aβ monomers. This aggregation of Aβ and NFT is promoted by various genes like BACE1, ADAM10, PIN1, GSK-3, APOE, PPARα, etc. Identification of these genes can discover several therapeutic targets that can be useful in studying pathogenesis and underlying treatments. Melatonin modulates the activities of these genes, thereby reducing Aβ production and increasing its clearance. Melatonin also reduces the expression of APP by attenuating cAMP, thereby enhancing the nonamyloidogenic process. Present communication explored and discussed the neuroprotective role of melatonin against Aβ-dependent AD pathogenesis. The manuscript also discussed potential molecular and genetic mechanisms of melatonin in the production and clearance of Aβ that could ameliorate neurotoxicity.

Traumatic brain injury is an outcome of external forces' physical or mechanical impact on the brain. Thus, the silent epidemic has complex pathophysiology affecting the brain along with extracranial or systemic complications in more than one organ system, including the heart, lungs, liver, kidney, gastrointestinal and endocrine system which is referred to as Multi-Organ Dysfunction Syndrome. It is driven by three interconnected mechanisms, such as systemic hyperinflammation, paroxysmal sympathetic hyperactivity, and immunosuppression-induced sepsis. These multifaceted pathologies accelerate the risk of mortality in clinical settings by interfering with the functions of distant organs through hypertension, cardiac arrhythmias, acute lung injury, neurogenic pulmonary edema, reduced gastrointestinal motility, Cushing ulcers, acute liver failure, acute kidney injury, coagulopathy, endocrine dysfunction, and many other impairments. The pharmaceutical treatment approach for this is highly specific in its mode of action and linked to various side effects, including hallucinations, seizures, anaphylaxis, teeth, bone staining, etc. Therefore, alternative natural medicine treatments are widely accepted due to their broad complementary or synergistic effects on the physiological system with minor side effects. This review is a compilation of the possible mechanisms behind the occurrence of multiorgan dysfunction and reported medicinal plants with organ protective activity that not yet been explored against traumatic brain injury and thereby highlighting the marked possibilities of their effectiveness in the management of multiorgan dysfunction. As a result, we attempted to respond to the hypothesis against using medicinal plants to treat neurodegenerative diseases.

Background: Circular RNAs (circRNAs), as covalently closed single-stranded noncoding RNA molecules, have been recently identified to involve in several biological processes, principally through targeting microRNAs. Among various neurodegenerative diseases (NDs), accumulating evidence has proposed key roles for circRNAs in the pathogenesis of Alzheimer’s disease (AD); although the exact relationship between these RNA molecules and AD progression is not clear, they have been believed to mostly act as miRNA sponges or gene transcription modulators through the correlating with multiple proteins, involved in the accumulation of Amyloid β (Aβ) peptides, as well as tau protein, as AD’s pathological hallmark. More interestingly, circRNAs have also been reported to play diagnostic and therapeutic roles during the AD progression. Objective: The literature review indicated that circRNAs could essentially contribute to the onset and development of AD. Thus, in the current review, the circRNAs’ biogenesis and functions are addressed at first, and then the interplay between particular circRNAs and AD is comprehensively discussed. Eventually, the diagnostic and therapeutic significance of these noncoding RNAs is briefly highlighted. Results: A large number of circRNAs are expressed in the brain. Thereby, these RNA molecules are noticed as potential regulators of neural functions in healthy circumstances, as well as in neurological disorders. Moreover, circRNAs have also been reported to have potential diagnostic and therapeutic capacities in relation to AD, the most prevalent ND. Conclusion: CircRNAs have been shown to act as sponges for miRNAs, thereby regulating the function of related miRNAs, including oxidative stress, reduction of neuroinflammation, and the formation and metabolism of Aβ, all of which developed in AD. CircRNAs have also been proposed as biomarkers that have potential diagnostic capacities in AD. Despite these characteristics, the use of circRNAs as therapeutic targets and promising diagnostic biomarkers will require further investigation and characterization of the function of these RNA molecules in AD.

Progressive neurodegenerative disorders such as Parkinson’s disease (PD) have continued to baffle medical science, despite strides in the understanding of their pathology. The inability of currently available therapies to halt disease progression is a testament to an incomplete understanding of pathways crucial to disease initiation, progression and management. Science has continued to link the activities and equilibrium of the gut microbiome to the health and proper functioning of brain neurons. They also continue to stir interest in the potential applications of technologies that may shift the balance of the gut microbiome towards achieving a favourable outcome in PD management. There have been suggestions that an improved understanding of the roles of the gut microbiota is likely to lead to the emergence of an era where their manipulation becomes a recognized strategy for PD management. This review examines the current state of our journey in the quest to understand how gut microbiota can influence several aspects of PD. We highlight the relationship between the gut microbiome/ microbiota and PD pathogenesis, as well as preclinical and clinical evidence evaluating the effect of postbiotics, probiotics and prebiotics in PD management. This is with a view to ascertaining if we are at the threshold of discovering the application of a usable tool in our quest for disease modifying therapies in PD.

Background: Peripheral facial nerve palsy is a relatively frequent, rather idiopathic, and isolated nonprogressive disorder with a tendency toward spontaneous recovery in children. It is primarily characterized by unilateral paresis or paralysis of the mimic musculature, affecting verbal communication, social interactions, and quality of life. Objective: This study aimed to evaluate the clinical aspects and efficacy of different therapeutic modalities in the population of children and adolescents with acute peripheral facial nerve palsy, the quality and recovery rate in comparison to different therapy modalities and etiological factors as well as to determine parameters of recovery according to the age of patients. Methods: The retrospective study included children and adolescents (n=129) with an acute onset of peripheral facial nerve palsy, diagnosed and treated in the Clinic of Neurology and Psychiatry for Children and Youth in Belgrade (2000-2018). The mean age of the patients was 11.53 years (SD±4.41). Gender distribution was 56.6% female and 43.4% male patients. Results: There were 118 (91.5%) patients with partial and 11 (8.5%) patients with complete paralysis. Left-sided palsy occurred in 67 (51.9%) patients, right-sided in 58 (45.0%), while there were 4 (3.1%) bilateral paralyses. The most common etiological factor was idiopathic (Bell’s palsy), i.e., 74 (57.4%) patients, followed by middle ear infections, i.e., 16 (12.4%). Regardless of etiology, age, and therapy protocols, there was a significant recovery in most of the patients (p<0.001), without significant differences in recovery rate. Comparison of inpatient and outpatient populations showed significant differences regarding the number of relapses, the severity of clinical presentation, and the recovery rate in relation to etiology. Conclusion: Bell’s palsy is shown to be the most common cause of peripheral facial nerve palsy in children and adolescents, regardless of gender. It is followed by mid-ear infections, respiratory infections, and exposure to cold. Most children and adolescents recovered three weeks after initial presentation, regardless of etiology, age, and therapy.

Aims: To determine the efficacy of XPro1595 to improve pathophysiological and functional outcomes in a mouse model of traumatic brain injury (TBI). Background: Symptoms associated with TBI can be debilitating, and treatment without off-target side effects remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of TBI. Objectives: Use XPro1595 to determine whether injury-induced solTNF promotes hippocampal inflammation and dendritic plasticity and associated functional impairments. Methods: Mild-to-moderate traumatic brain injury (CCI model) was induced in adult male C57Bl/6J WT and Thy1-YFPH mice, with XPro1595 (10 mg/kg, S.C.) or vehicle being administered in a clinically relevant window (60 minutes post-injury). The animals were assessed for differences in neurological function, and hippocampal tissue was analyzed for inflammation and glial reactivity, as well as neuronal degeneration and plasticity. Results: We report that unilateral CCI over the right parietal cortex in mice promoted deficits in learning and memory, depressive-like behavior, and neuropathic pain. Using immunohistochemical and Western blotting techniques, we observed the cortical injury promoted a set of expected pathophysiology’s within the hippocampus consistent with the observed neurological outcomes, including glial reactivity, enhanced neuronal dendritic degeneration (dendritic beading), and reduced synaptic plasticity (spine density and PSD-95 expression) within the DG and CA1 region of the hippocampus, that were prevented in mice treated with XPro1595. Conclusion: Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of brain-injured mice, which provides support for its use in patients with TBI.

Background: Gelidium amansii has been gaining profound interest in East Asian countries due to its enormous commercial value for agar production and its extensive pharmacological properties. Previous studies have shown that the ethanol extract of Gelidium amansii (GAE) has promising neurotrophic effects in in vitro conditions. Objectives: The present study aimed to investigate the protective effects of GAE against scopolamineinduced cognitive deficits and its modulatory effects on hippocampal plasticity in mice. Methods: For memory-related behavioral studies, the passive avoidance test and radial arm maze paradigm were conducted. The brain slices of the hippocampus CA1 neurons of experimental mice were then prepared to perform Golgi staining for analyzing spine density and its characteristic shape and immunohistochemistry for assessing the expression of different pre- and postsynaptic proteins. Results: Following oral administration of GAE (0.5 mg/g body weight), mice with memory deficits exhibited a significant increase in the latency time on the passive avoidance test and a decrease in the number of working and reference memory errors and latency time on the radial arm maze test. Microscopic observations of Golgi-impregnated tissue sections and immunohistochemistry of hippocampal slices showed that neurons from GAE-treated mice displayed higher spine density and spine dynamics, increased synaptic contact, and the recruitment of memory-associated proteins, such as N-methyl-Daspartate receptors (NR2A and NR2B) and postsynaptic density-95 (PSD-95) when compared with the control group. Conclusion: With these memory-protective functions and a modulatory role in underlying memoryrelated events, GAE could be a potential functional food and a promising source of pharmacological agents for the prevention and treatment of memory-related brain disorders.