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Background: Melatonin is responsible for regulating the sleep-wake cycle and circadian rhythms in mammals. Tramadol, a synthetic opioid analgesic, is used to manage moderate to severe pain but has a high potential for abuse and dependence. Studies have shown that melatonin could be a potential modulator to reduce tramadol addiction. Methods: Male Wistar rats were used to investigate the effect of melatonin on tramadol-induced place preference. The rats were divided into four groups: control, tramadol, tramadol + melatonin (single dose), and tramadol + melatonin (repeated doses). Tramadol was administered intraperitoneally at 40 mg/kg, while melatonin was administered at 50 mg/kg for both the single dose and repeateddose groups. The study consisted of two phases: habituation and acquisition. Results: Tramadol administration produced conditioned place preference (CPP) in rats, indicating rewarding effects. However, melatonin administration blocked tramadol-induced CPP. Surprisingly, repeated doses of melatonin were ineffective and did not reduce the expression of CPP compared to that of the single dose administration. Conclusion: The study suggests that melatonin may be a potential therapeutic option for treating tramadol addiction. The results indicate that melatonin attenuates the expression of tramadol-induced CPP, supporting its uses as an adjunct therapy for managing tramadol addiction. However, further studies are needed to investigate its effectiveness in humans. [ABSTRACT FROM AUTHOR]

Introduction: This research was conducted to validate the folkloric use of Quercus leucotrichophora (QL) leaf extracts against inflammation and arthritis and to determine the chemical composition using HPLC. Method: The aqueous and methanolic extracts of QL were evaluated by in vitro antioxidant, anti-inflammatory (inhibition of protein denaturation and membrane stabilization) assays, and in vivo anti-inflammatory (carrageenan and xylene-induced edema) and anti-arthriticmodels. For anti-arthritic potential, 0.1 mL Complete Freund's Adjuvant (CFA) was inoculated into the left hind paw of a Wistar rat on day 1, and oral dosing with QL methanolic extract (QLME) at 150, 300, and 600mg/kg was begun at day 8 till the 28th day in all groups, except disease control that was given distilled water, while methotrexate was given as standard treatment. Results and discussion: There was a noteworthy (p < 0.05-0.0001) restoration in body weight, paw edema, arthritic index, altered blood parameters, and oxidative stress biomarkers in treated rats as compared to the diseased group. Moreover, QLME treatment significantly (p < 0.0001) downregulated TNF-α, IL-6, IL-1β, COX-2, and NF-κB, while significantly (p < 0.0001) upregulating IL-10, I-κB, and IL-4 in contrast to the diseased group. The QLME exhibited no mortality in the acute toxicity study. It was concluded that QLME possessed substantial anti-oxidant, anti-inflammatory, and antiarthritic potential at all dosage levels prominently at 600 mg/kg might be due to the presence of quercetin, gallic, sinapic, and ferulic acids. [ABSTRACT FROM AUTHOR]

Stimulation of remyelination is critical for the treatment of multiple sclerosis (MS) to alleviate symptoms and protect the myelin sheath from further damage. The current study aimed to investigate the possible therapeutic effects of combining vitamin D3 (Vit D3) and siponimod (Sipo) on enhancing remyelination and modulating microglia phenotypes in the cuprizone (CPZ) demyelination mouse model. The study was divided into two stages; demyelination (first 5 weeks) and remyelination (last 4 weeks). In the first 5 weeks, 85 mice were randomly divided into two groups, control (n = 20, standard rodent chow) and CPZ (n = 65, 0.3% CPZ mixed with chow for 6 weeks, followed by 3 weeks of standard rodent chow). At week 5, the CPZ group was re-divided into four groups (n = 14) for remyelination stages; untreated CPZ (0.2 ml of CMC orally), CPZ+Vit D3 (800 IU/kg Vit D3 orally), CPZ+Sipo (1.5 mg/kg Sipo orally), and CPZ+Vit D3 (800 IU/kg Vit D3) + Sipo (1.5 mg/kg Sipo orally). Various behavioral tasks were performed to evaluate motor performance. Luxol Fast Blue (LFB) staining, the expression level of myelin basic protein (MBP), and M1/M2 microglia phenotype genes were assessed in the corpus callosum (CC). The results showed that the combination of Vit D3 and Sipo improved behavioral deficits, significantly promoted remyelination, and modulated expression levels of microglia phenotype genes in the CC at early and late remyelination stages. These results demonstrate for the first time that a combination of Vit D3 and Sipo can improve the remyelination process in the cuprizone (CPZ) mouse model by attenuating the M1 microglia phenotype. This may help to improve the treatment of MS patients. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) places a heavy load on healthcare systems worldwide. Despite significant advancements in care, the TBI-relatedmortality is 30-50% and in most cases involves adolescents or young adults. Previous literature has suggested that neutrophil-to-lymphocyte ratio (NLR) may serve as a sensitive biomarker in predicting clinical outcomes following TBI. With conclusive evidence in this regard lacking, this study aimed to systematically review all original studies reporting the effectiveness of NLR as a predictor of TBI outcomes. A systematic search of eight databases was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement (PRISMA) recommendations. The risk of bias was assessed using the Quality in Prognostic Studies (QUIPS) tool. Eight studies were ultimately included in the study. In most of the studies interrogated, severity outcomes were successfully predicted by NLR in both univariate and multivariate prediction models, in different follow-up durations up to 6 months. A high NLR at 24 and 48 h after TBI in pediatric patients was associated with worse clinical outcomes. On pooling the NLR values within studies assessing its association with the outcome severity (favorable or not), patients with favorable outcomes had 37% lower NLR values than those with unfavorable ones (RoM= 0.63; 95% CI = 0.44-0.88; p = 0.007). However, there were considerable heterogeneity in effect estimates (I² = 99%; p < 0.001). Moreover, NLR was a useful indicator of mortality at both 6-month and 1-year intervals. In conjunction with clinical and radiographic parameters, NLR might be a useful, inexpensive marker in predicting clinical outcomes in patients with TBI. However, the considerable heterogeneity in current literature keeps it under investigation with further studies are warranted to confirm the reliability of NLR in predicting TBI outcomes. [ABSTRACT FROM AUTHOR]

Ever since the dawn of antiquity, people have strived to improve their cognitive abilities. From the advent of the wheel to the development of artificial intelligence, technology has had a profound leverage on civilization. Cognitive enhancement or augmentation of brain functions has become a trending topic both in academic and public debates in improving physical and mental abilities. The last years have seen a plethora of suggestions for boosting cognitive functions and biochemical, physical, and behavioral strategies are being explored in the field of cognitive enhancement. Despite expansion of behavioral and biochemical approaches, various physical strategies are known to boost mental abilities in diseased and healthy individuals. Clinical applications of neuroscience technologies offer alternatives to pharmaceutical approaches and devices for diseases that have been fatal, so far. Importantly, the distinctive aspect of these technologies, which shapes their existing and anticipated participation in brain augmentations, is used to compare and contrast them. As a preview of the next two decades of progress in brain augmentation, this article presents a plausible estimation of themany neuroscience technologies, their virtues, demerits, and applications. The review also focuses on the ethical implications and challenges linked to modern neuroscientific technology. There are times when it looks as if ethics discussions are more concerned with the hypothetical than with the factual. We conclude by providing recommendations for potential future studies and development areas, taking into account future advancements in neuroscience innovation for brain enhancement, analyzing historical patterns, considering neuroethics and looking at other related forecasts. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive functions like thinking, memory, reasoning, behavioral abilities, and social skills thus affecting the ability of a person to perform normal daily functions independently. There is no definitive cure for this disease, and treatment options available for the management of the disease are not very effective as well. Based on histopathology, AD is characterized by the accumulation of insoluble deposits of amyloid beta (Ab) plaques and neurofibrillary tangles (NFTs). Although several molecular events contribute to the formation of these insoluble deposits, the aberrant post-translational modifications (PTMs) of AD-related proteins (like APP, Aβ, tau, and BACE1) are also known to be involved in the onset and progression of this disease. However, early diagnosis of the disease as well as the development of effective therapeutic approaches is impeded by lack of proper clinical biomarkers. In this review, we summarized the current status and clinical relevance of biomarkers from cerebrospinal fluid (CSF), blood and extracellular vesicles involved in onset and progression of AD. Moreover, we highlight the effects of several PTMs on the AD-related proteins, and provide an insight how these modifications impact the structure and function of proteins leading to AD pathology. Finally, for disease-modifying therapeutics, novel approaches, and targets are discussed for the successful treatment and management of AD. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of the brain that manifests as dementia, disorientation, difficulty in speech, and progressive cognitive and behavioral impairment. The emerging therapeutic approach to AD management is the inhibition of β-site APP cleaving enzyme-1 (BACE1), known to be one of the two aspartyl proteases that cleave β-amyloid precursor protein (APP). Studies confirmed the association of high BACE1 activity with the proficiency in the formation of β-amyloid-containing neurotic plaques, the characteristics of AD. Only a few FDA-approved BACE1 inhibitors are available in the market, but their adverse off-target effects limit their usage. In this paper, we have used both ligand-based and target-based approaches for drug design. The QSAR study entails creating a multivariate GA-MLR (Genetic Algorithm-Multilinear Regression) model using 552 molecules with acceptable statistical performance (R² = 0.82, Q²loo = 0.81). According to the QSAR study, the activity has a strong link with various atoms such as aromatic carbons and ring Sulfur, acceptor atoms, sp2-hybridized oxygen, etc. Following that, a database of 26,467 food compounds was primarily used for QSAR-based virtual screening accompanied by the application of the Lipinski rule of five; the elimination of duplicates, salts, and metal derivatives resulted in a truncated dataset of 8,453 molecules. The molecular descriptor was calculated and a well-validated 6-parametric version of the QSAR model was used to predict the bioactivity of the 8,453 food compounds. Following this, the food compounds whose predicted activity (pKi) was observed above 7.0 M were further docked into the BACE1 receptor which gave rise to the Identification of 4-(3,4-Dihydroxyphenyl)-2-hydroxy-1H-phenalen-1-one (PubChem I.D: 4468; Food I.D: FDB017657) as a hit molecule (Binding Affinity = −8.9 kcal/mol, pKi = 7.97 nM, Ki = 10.715 M). Furthermore, molecular dynamics simulation for 150 ns and molecular mechanics generalized born and surface area (MMGBSA) study aided in identifying structural motifs involved in interactions with the BACE1 enzyme. Molecular docking and QSAR yielded complementary and congruent results. The validated analyses can be used to improve a drug/lead candidate’s inhibitory efficacy against the BACE1. Thus, our approach is expected to widen the field of study of repurposing nutraceuticals into neuroprotective as well as anti-cancer and anti-viral therapeutic interventions. [ABSTRACT FROM AUTHOR]

Opioid addiction remains a widespread issue despite continuous attempts by the FDA to help maintain abstinence. Melatonin is a neurohormone considered to be involved only in the neuroendocrine and reproductive systems; however, recent reports have demonstrated its potential to attenuate drug addiction and dependence. Cumulative studies have suggested that melatonin can attenuate the rewarding effects of several drugs of abuse, including opioids. This study aimed to investigate the effect of melatonin (50 mg/kg) on morphine (5 mg/kg) to produce place preference. We also investigated the effect of melatonin and morphine on the expression of GLT-1, BDNF, NF-κB, and CREB within the nucleus accumbens. Male Wistar rats were divided into control, morphine, melatonin, and the morphine + melatonin groups. The study involved a two-phase habituation phase from day 1 to day 3 and an acquisition phase from day 5 to day 14. The conditioned place preference (CPP) score, distance traveled, resting time, ambulatory count, and total activity count were measured for all animals. Rats that received morphine showed a significant increase in CPP score compared to those in the control group. Morphine treatment reduced the mRNA expression of GLT-1, BDNF, and CREB and increased that of NF-κB. However, melatonin treatment administered 30 min before morphine treatment attenuated morphine place preference and reversed GLT-1, BDNF, NF-κB, and CREB expression levels. In conclusion, the study results indicate, for the first time, the new potential targets of melatonin in modulating morphine-induced CPP. [ABSTRACT FROM AUTHOR]

Atypical antipsychotic drugs are commonly associated with undesirable side effects including body weight gain (BWG) and metabolic deficits. Many pharmacological interventions have been tested in an attempt to minimize or prevent these side effects. Preliminary evidence suggests that antidiabetic drugs may be effective in attenuating antipsychotic-induced BWG. In the current study, we examined the effect of an antidiabetic drug empagliflozin (EMPA) on BWG induced by anatypical antipsychotic drug olanzapine (Ola) in female and male Wistar rats. Rats were divided into six groups based on the dose they received: group 1 (female control), group 2 (female EMPA, 20 mg/kg; IG), group 3 (female Ola, 4 mg/kg; IP), group 4 (female Ola, 4 mg/kg; IP + EMPA, 20 mg/kg; IG), group 5 (male control), and group 6 (male Ola, 4 mg/kg; IP). Ola induced sustained increase in BWG. The subsequent treatment of Group 3 and 4 with EMPA attenuated the Ola-induced BWG in female Wistar rats. In terms of the gender difference between female and male Wistar rats, the male control group 5 gained more weight throughout the study as compared to the female control group 1. Similarly, the male Ola group 6 gained more weight throughout the study as compared to the female Ola group 3. However, Ola did not cause any weight difference between male rats treated with Ola in comparison with male control group, thus showing a significant gender difference regarding body weight between male and female Wistar rats regardless of Ola administration. In addition, the present findings showed that EMPA effectively attenuates the Ola induced BWG in female Wistar rats. These novel findings should help to better understand the underlying molecular and behavioral mechanisms contributing to the observed increase in body weight after treatment with Ola and other atypical antipsychotic drugs across male and female rats. [ABSTRACT FROM AUTHOR]