CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 22, Issue 8, 2023

Translational psychiatry has been a hot topic in neurosciences research. The authors present a commentary on the relevant findings from a transdiagnostic study applicable to clinic practice. Additional discussion on conceptual and clinical insight into this current broad line of research is explored in the integration of multi-level paradigm in Psychiatry research.

Intranasal delivery has great potential to cross the blood-brain barrier and deliver the drug molecule into the central nervous system faster than the traditional methods. The olfactory neuronal and trigeminal pathways both are involved in intranasal delivery. The nano-technology is an innovative strategy for the nose to brain delivery. The mucoadhesive nanoemulsion formulation is a modified technology that increases the duration of drug accumulation and provides prolonged delivery at a targeted site. The nanoemulsion formulation oil, surfactant, and co-surfactant components maintain lower surface tension and particle coalescence. The globule dimension and zeta potential are affected in brain targeting. The globule size of the innovative formulation should be < 200 nm for drug permeation because, in humans, the average axon magnitude ranges from around 100 to 700 nm. Furthermore, modified technology of nanoemulsions like nanogel and nanoemulsion in-situ gel provide a great advantage to cure neurodegenerative disorders. Therefore, focusing on the innovative pharmaceutical approaches of nanoemulsion in intranasal drug delivery, the current review provides insight into the applications of nanoemulsion in neurodegenerative disorders like Parkinson's disease, which are due to the depletion of dopamine in substania nigra resulting in cardinal motor activity bradykinesia and tremors. The review also touches upon the pathways for intranasal delivery of nanoemulsion, the pathogenesis of Parkinson's disease, and the future direction of the research on intranasal nanoemulsion.

The gut microbiome is a complicated ecosystem of around a hundred billion symbiotic bacteria cells. Bidirectional communication between the gut and the brain is facilitated by the immune system, the enteric nervous system, the vagus nerve, and microbial compounds such as tryptophan metabolites and short-chain fatty acids (SCFAs). The current study emphasises the relationship of the gut-brain axis with cognitive performance and elucidates the underlying biological components, with a focus on neurotransmitters such as serotonin, indole derivatives, and catecholamine. These biological components play important roles in both the digestive and brain systems. Recent research has linked the gut microbiome to a variety of cognitive disorders, including Alzheimer's (AD). The review describes the intriguing role of the gut-brain axis in recognition memory depending on local network connections within the hippocampal as well as other additional hippocampal portions of the Papez circuit. The available data from various research papers show how the gut microbiota might alter brain function and hence psychotic and cognitive illnesses. The role of supplementary probiotics is emphasized for the reduction of brain-related dysfunction as a viable strategy in handling cognitive disorders. Further, the study elucidates the mode of action of probiotics with reported adverse effects.

Objectives: Major depressive disorder (MDD) has been reported to affect an increasing number of individuals due to the modern lifestyle. Because of its complicated mechanisms and recurrent attacks, MDD is considered a refractory chronic disease. Although the mainstream therapy for MDD is chemical drugs, they are not a panacea for MDD because of their expensiveness, associated serious adverse reactions, and endless treatment courses. Hence, we studied three kinds of herbal medicines, namely, Panax ginseng C.A. Mey (PGM), Bupleurum chinense DC (BCD), and Gastrodia elata Blume (GEB), and reviewed the mechanisms underlying their antidepressant properties to provide a reference for the development of antidepressants and clinical medications. Methods: An extensive range of medicinal, clinical, and chemistry databases and search engines were used for our literature search. We searched the literature using certain web literature search engines, including Google Scholar, PubMed, Science Direct, CNKI (China National Knowledge Infrastructure), and Web of Science. Results: Experimental research found that active compounds of these three medicines exhibited good antidepressant effects in vivo and in vitro. Clinical investigations revealed that single or combined treatment of these medicines improved certain depressive symptoms. Antidepressant mechanisms are summarized based on this research. Conclusion: The antidepressant mechanism of these three medicines includes but is not limited to ameliorating inflammation within the brain, reversing the hypothalamic-pituitary adrenal axis (HPA) system hyperfunction, inhibiting monoamine neurotransmitters reuptake, anti-neuron apoptosis and preventing neurotoxicity, and regulating depressive-related pathways such as the BDNF pathway and the PI3K/Akt/mTOR pathway.

Background: Neurodegenerative disorders may depend upon a misregulation of the pathways which sustain neurodevelopmental control. In this context, this review article focuses on Friedreich ataxia (FA), a neurodegenerative disorder resulting from mutations within the gene encoding the Frataxin protein, which is involved in the control of mitochondrial function and oxidative metabolism. Objective: The specific aim of the present study concerns the FA molecular and cellular substrates, for which available transgenic mice models are proposed, including mutants undergoing misexpression of adhesive/morphoregulatory proteins, in particular belonging to the Contactin subset of the immunoglobulin supergene family. Methods: In both mutant and control mice, neurogenesis was explored by morphological/morphometric analysis through the expression of cell type-specific markers, including b-tubulin, the Contactin-1 axonal adhesive glycoprotein, as well as the Glial Fibrillary Acidic Protein (GFAP). Results: Specific consequences were found to arise from the chosen misexpression approach, consisting of a neuronal developmental delay associated with glial upregulation. Protective effects against the arising phenotype resulted from antioxidants (essentially epigallocatechin gallate (EGCG)) administration, which was demonstrated through the profiles of neuronal (b-tubulin and Contactin 1) as well as glial (GFAP) markers, in turn indicating the concomitant activation of neurodegeneration and neuro repair processes. The latter also implied activation of the Notch-1 signaling. Conclusion: Overall, this study supports the significance of changes in morphoregulatory proteins expression in the FA pathogenesis and of antioxidant administration in counteracting it, which, in turn, allows to devise potential therapeutic approaches.

Sleep deprivation (SD) (also referred as insomnia) is a condition in which individuals fail to get enough sleep due to excessive yawning, facing difficulty to learn new concepts, experiencing forgetfulness as well as depressed mood. This could occur due to several possible reasons, including medications and stress (caused by shift work). Despite the fact that sleep is important for normal physiology, it currently affects millions of people around the world, especially the US (70 million) and Europe (45 million). Due to increased work demand nowadays, lots of people are experiencing sleep deprivation hence, this could be the reason for several car accidents followed by death and morbidity. This review highlighted the impact of SD on neurotransmitter release and functions, theories (Flip-flop theory, oxidative stress theory, neuroinflammation theory, neurotransmitter theory, and hormonal theory) associated with SD pathogenesis; apart from this, it also demonstrates the molecular pathways underlying SD (PI3K and Akt, NF-ΚB, Nrf2, and adenosine pathway. However, this study also elaborates on the SD-induced changes in the level of neurotransmitters, hormonal, and mitochondrial functions. Along with this, it also covers several molecular aspects associated with SD as well. Through this study, a link is made between SD and associated causes, which will further help to develop a potential therapeutic strategy against SD.

Background: Alzheimer’s Disease (AD) is the most rampant neurodegenerative disorder which has caused havoc worldwide. More than a century has passed since the first case of AD was reported, but still, no stable treatment is known to humanity. The available medications only provide temporary relief and are not a cure for the disease. The hunt for advanced techniques in drug development has paved the way for drug repurposing, i.e., repositioning or reutilizing drugs as an innovative approach. Methodology: Several drugs which were repurposed for AD were collected by following PRISMA 2020 systemic review. Databases like PubMed, ScienceDirect, JSTOR, and SciELO were used for data extraction. Further, the Drugbank database was used to download all the identified drugs. Later, the Swiss Target Prediction tool was used to identify protein receptors for these drugs and the biological pathway followed by them. Results: Drugs like Zileuton, Salbutamol, Baricitinib, Carmustine, Paclitaxel, and Nilotinib were observed to be involved in regulation of neurotransmitters. Similarly, Metformin, Liraglutide, UDCA, and Bexarotene are involved in protein kinase cascades which also is one of the prime processes in metabolic disorders like AD. Furthermore, drugs like Rosiglitazone, Pioglitazone, and Lonafarnib are involved in interleukin-3 biosynthetic processes, which is again one of the most important processes studied in AD treatment. Conclusion: The study concluded that the reviewed drugs that follow similar biological and molecular processes could be repurposed for AD if chosen judiciously with current medications and thus, drug repurposing is a promising approach that can be utilized to find a cure for AD within a brief time and fewer resources compared to de novo drug synthesis. Although certain loopholes still need to be worked upon, the technique has great prospects. Furthermore, in silico methods can be utilized to justify the findings and identify the best drug candidate.

Background: Alzheimer's disease (AD) is a degenerative neurological disorder that impairs memory, cognitive abilities, and the ability to do everyday activities. This neurodegenerative disease is growing increasingly common as the world's population ages. Here, we reviewed some of the key findings showing the function of Aβ peptide, oxidative stress, free radical damage Triggering Receptors Expressed cn Myeloid Cells 2 (TREM2), Nitric Oxide (NO) and gut microbiota in the aetiology of AD. Methods: The potentially relevant online medical databases, namely PubMed, Scopus, Google Scholar, Cochrane Library, and JSTOR, were exhaustively researched. In addition, the data reported in the present study were primarily intervened on the basis of the timeline selected from 1 January 2000 to 31 October 2021. The whole framework was designed substantially based on key terms and studies selected by virtue of their relevance to our investigations. Results: Findings suggested that channels of free radicals, such as transition metal accumulation and genetic factors, are mainly accountable for the redox imbalance that assist to understand better the pathogenesis of AD and incorporating new therapeutic approaches. Moreover, TREM2 might elicit a protective function for microglia in AD. NO causes an increase in oxidative stress and mitochondrial damage, compromising cellular integrity and viability. The study also explored that the gut and CNS communicate with one another and that regulating gut commensal flora might be a viable therapeutic for neurodegenerative illnesses like AD. Conclusion: There are presently no viable therapies for Alzheimer's disease, but recent breakthroughs in our knowledge of the disease's pathophysiology may aid in the discovery of prospective therapeutic targets.

Background: Safer and effective alternatives to manage nicotine dependence are still required. Preliminary studies have shown the potential of virgin coconut oil (VCO) to be used in dependence treatment. Objective: To assess the VCO effect administered for 14 days on nicotine dependence and quality of life. Methods: Forty smoking subjects participated in an open-label, single-center, pre/post-intervention study, and were required to take 15 ml VCO twice daily for 14 days. They were evaluated with the Fagerstrom Test for Nicotine Dependence (FTND) for nicotine dependence intensity and EuroQolvisual analogue scales (EQ VAS) for quality of life. Results: The VCO regimen improved FTND (0.53 points decrease, p<0.05) and EQ-VAS (5.85 points increase p<0.01) scores. Adverse events were all mild. Conclusion: Results of the present study suggest that VCO has the potential to be a safe and effective adjunct therapy for the management of nicotine dependence.

Background and Objective: Recent studies have shown that lithium treatment can reduce symptoms of Alzheimer’s disease (AD) and Autism Spectrum Disorder (ASD). However, the present lithium salts clinically available have serious short-term and long-term side effects, requiring frequent monitoring of blood chemistry and plasma lithium levels to avoid toxicity. Consequently, there is a demand for a safer and more effective lithium formulation to treat these diseases. Methods: Hence, we firstly synthesized lithium cholesterol sulfate (LiCS) and compared its pharmacological effects with that of lithium chloride (LiCl) and sodium cholesterol sulfate (NaCS) on markers of neurodegenerative disease in cell cultures. Results: LiCS was more potent than LiCl in increasing inhibitory GSK3β (Ser9) phosphorylation (pGSK3β) in both CHO and SH-SY5Y cells. These agents dose-dependently increased pGSK3β, starting at 10 μM for LiCS and 60 μM for LiCl and maximally by approximately 100% at 60 μM for LiCS and 1.25 mM for LiCl, without altering total GSK3β levels. In HEK293/tau cells, LiCS reduced tau (Thr231) phosphorylation (ptau) starting at 10 μM and maximally by 63% at 40 μM without altering total tau levels, but ptau levels were not altered by LiCl at any dose between 60 μM and 1.25 mM. In BV2 cells, LiCS and LiCl decreased LPS-induced TNFα levels, starting at 20 μM for LiCS and 5 mM for LiCl, and maximally by approximately 30% at 80 μM for LiCS and 20 mM for LiCl. NaCS at any dose between 5 and 90 μM did not alter pGSK3β, ptau or LPS-induced TNFα. Conclusion: LiCS may become a new drug with good pharmacological potential for the treatment of neurodegenerative disorders, such as AD and ASD, by allowing lithium to more readily access intracellular pathological processes.

Background: Endoscopy provides valuable diagnostic information and intervention therapies for gastroenterologists. Therefore, various drugs have been used to induce sedation in patients undergoing endoscopy, whereas none have been considered preferred by endoscopists. In the current study, we decided to use the combination of magnesium sulfate, ketamine, and their synergistic effects for creating partial analgesia to increase the satisfaction of endoscopists and patients. Methods: This study is a Double-Blind Randomized Clinical Trial that investigates the sedative effect of ketamine, magnesium sulfate, and propofol in endoscopy. Patients were selected from individuals over 12 years old and with American Society of Anesthesia (ASA) physical status I or II. The study was performed on 210 patients classified as ASA (I have no underlying disease) or II (with underlying controlled disease). The whole group was relieved of pain through sedation according to Ramsay criteria, satisfaction with the operation, duration, recovery, nausea and vomiting, hypotension, and decreased oxygen saturation were compared. Results: A total of 155 patients were enrolled in our study, including 51 patients (midazolam and propofol), 55 patients (midazolam and ketamine), and 49 patients (midazolam and ketamine and magnesium). The results showed that preoperative heart rate, intraoperative systolic blood pressure, intraoperative diastolic blood pressure, postoperative heart rate, postoperative systolic blood pressure, and postoperative heart rate were significantly different between the groups. Conclusion: The satisfaction of the endoscopic was achieved to a great extent, mainly in the group receiving midazolam and propofol and in the group receiving midazolam and ketamine. In most cases, the satisfaction of the endoscopic was acceptable, and the low satisfaction of the endoscopic was more in the group receiving midazolam. Ketamine and magnesium were observed. The two compounds midazolam-ketamine, and midazolam-propofol, have a more favorable effect than the combination of midazolam, ketamine, and magnesium.