Clinical efficacy and safety of melatonin supplementation in multiple sclerosis: a systematic review.

BACKGROUND: Melatonin is a neurohormone secreted predominantly by the pineal gland that is demonstrated to be associated with the pathogenesis of multiple sclerosis (MS). This research desires to evaluate the tolerability and beneficial effects of exogenous melatonin supplementations in patients with MS. METHODS: This study was executed following the PRISMA 2020 statement. Both observational and interventional studies which reported the clinical effectiveness and/or safety of melatonin supplementation in patients with MS were included in this systematic review. Ovid, PubMed, Scopus, Embase, and Web of Science databases were searched and the risk of bias in included studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools based on study design. RESULTS: Out of 1304 results of database searches, finally, 14 articles, including 7 randomized controlled trials (RCTs), 6 case-control studies, and one quasi-experimental study, were included based on the full-text review. Included phenotypes of MS were mostly relapsing-remitting MS (RRMS) (in 11 studies); it was secondary progressive MS (SPMS) in only one study, and two other studies had a mixture of the different phenotypes. The course of treatment with melatonin supplementation was between 2 weeks and 12 months. There were no substantial safety issues. Although melatonin was associated with enhanced oxidative stress and inflammation status, concerning the clinical benefits, limited studies suggested improvements in sleep conditions, cognitive outcomes, and fatigue in MS. DISCUSSION: There are insufficient data to support the regular melatonin prescription in MS. Limitations such as the small number of included studies, the diversity of the dosage, route, and duration of melatonin administration, and the diversity of assessment tests lead to unconvincing findings in this study. There is a need for future studies to achieve a comprehensive judgment on this subject.

Serum lipids and cognitive outcomes in multiple sclerosis; a systematic review and meta-analysis.

BACKGROUND: Cognitive impairment is highly prevalent in multiple sclerosis (MS) with poorly understood underlying mechanisms. Lipids are considered to be associated with MS progression through the inflammatory and oxidative stress pathways, brain atrophy, cellular signaling, and tissue physiology. In addition, serum lipids are proposed as a modifiable factor affecting the neuropsychiatric condition; therefore, this study aims to assess the association between serum lipid levels and cognitive outcomes in MS. METHODS: This study was carried out following the PRISMA 2020 statement. A systematic search was conducted in PubMed, Scopus, Web of Science, and Embase in March 2023, and the Joanna Briggs Institute (JBI)'s critical appraisal tools were utilized for risk of bias (RoB) assessments in the included studies. The quantitative synthesis was performed with the comprehensive meta-analysis (CMA3) software. RESULTS: Out of 508 screened records, 7 studies were eventually found to meet our inclusion criteria. In two studies, the course of MS in the sample of the study was only Relapsing-Remitting MS (RRMS), whereas the other five studies' sample was a combination of different phenotypes. Studies utilized different scales such as Minimal Assessment of Cognitive Function in MS (MACFIMS), Brief International Cognitive Assessment for MS (BICAMS), Montreal Cognitive Assessment (MoCA), Brief Repeatable Battery of Neuropsychological Tests (BRB-N) for cognitive evaluations. Dealing with possible confounders such as age, disease duration and level of disability was the most common possible source of bias in the included studies. One study revealed an inverse relationship between serum levels of apolipoproteins (including ApoA-I, ApoB, and ApoB/ApoA-I) and Symbol Digit Modalities Test (SDMT) scores. Also, a correlation between 24S-hydroxycholesterol (24OHC) serum concentrations and SDMT score was reported in one study. The association between serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) and different aspects of cognitive function was reported in the studies; however, serum levels of high-density lipoprotein cholesterol (HDL) were not found to be associated. The quantitative synthesis revealed a significant correlation between TC and the MoCA scores (r =-0.238; 95 %CI: -0.366 to -0.100; p-value = 0.001); however, the correlation between TG levels and MoCA were not statistically significant (r:-0.070; 95 %CI: -0.209 to 0.072; p-value: 0.334). In addition, the mata-analyses were not associated with significant findings regarding the correlation between lipid profiles (including HDL, LDL, TG, and TC) and other cognitive assessment scales including SDMT, Brief Visuospatial Memory Test (BVMT), and California Verbal Learning Test (CVLT) (p-values>0.05). DISCUSSION: Available evidence suggested a link between TC and LDL with cognitive outcomes of MS patients which was not evident in our quantitative synthesis. The limited number of studies, high RoB, different cognitive assessment scales and reporting methods, and the cross-sectional design of the included studies, were the main limitations that alleviate the clinical significance of the findings of this study and suggested further investigations on this topic. FUNDING AND REGISTRATION: The research protocol was approved and supported by the Student Research Committee, Tabriz University of Medical Sciences (grant number: 71,909). This study is registered in the international prospective register of systematic reviews (PROSPERO ID: CRD42023441625).

Metformin: new applications for an old drug.

Metformin is a biguanide, evolved as one of the most widely used medicines. The applications of this component include but are not limited to reducing blood glucose, weight loss, and polycystic ovary syndrome. Studies about other probable indications have emerged, indicating that this agent can also be utilized for other purposes. In this review, applications of metformin are noticed based on the current evidence. Metformin commonly is used as an off-label drug in non-alcoholic fatty liver disease (NAFLD), but it worsens inflammation and should not be used for this purpose, according to the latest research. Metformin decreased the risk of death in patients with liver cirrhosis. It is an effective agent in the prevention and improvement of survival in patients suffering hepatocellular carcinoma. There is evidence of the beneficial effects of metformin in colorectal cancer, early-stage prostate cancer, breast cancer, urothelial cancer, blood cancer, melanoma, and bone cancer, suggesting metformin as a potent anti-tumor agent. Metformin shows neuroprotective effects and provides a potential therapeutic benefit for mild cognitive impairment and Alzheimer's disease (AD). It also has been shown to improve mental function and reduce the incidence of dementia. Another condition that metformin has been shown to slow the progression of is Duchenne muscular dystrophy. Regarding infectious diseases, tuberculosis (TB) and coronavirus disease (COVID-19) are among the conditions suggested to be affected by metformin. The beneficial effects of metformin in cardiovascular diseases were also reported in the literature. Concerning renal function, studies showed that daily oral administration of metformin could ameliorate kidney fibrosis and normalize kidney structure and function. This study reviewed the clinical and preclinical evidence about the possible benefits of metformin based on recent studies. Numerous questions like whether these probable indications of metformin can be observed in non-diabetics, need to be described by future basic experiments and clinical studies.

The association of apolipoprotein E (ApoE) genotype and cognitive outcomes in multiple sclerosis; a systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a neuroinflammatory disorder commonly seen in young female adults. Cognitive impairment is one of the widespread symptoms of MS. In recent years multiple studies sought the possible risk factors for MS-related cognitive deficit. Apolipoprotein E (ApoE) genotype is one of the genetic factors which correlated significantly with cognitive status and it is a well-known risk factor for Alzheimer's Disease. In this systematic review and meta-analysis, we collected the current evidence to evaluate the association between the ApoE genotype and the cognitive outcomes in patients with MS. METHOD: Results of searches through Medline via PubMed, Scopus, and ISI web of science, as well as hand searching, were screened in the title/abstract and full-text stages. English observational studies in which the association between ApoE and cognitive outcomes, in patients with MS were included in this systematic review. Animal studies, conference abstracts, reviews, clinical trials, case reports, letters and withdrawn studies, were not included. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools and the meta-analysis was conducted with Comprehensive Meta-Analysis (CMA.2) software. The numbers of patients with impairment in both ApoE4+ and ApoE4- groups were utilized for the calculation of the odds ratios (ORs) with 95% confidence intervals (CI) and a 0.05 level of significance for p-value. RESULT: Out of 224 results of searching, 13 studies met the eligibility criteria and were included in our systematic review, and 5 of them were included in the quantitative synthesis. Eleven studies assessed the cognitive status of patients with MS in two groups of ApoE4+ and ApoE4- while 2 rests, reported the rate of ApoE4+ patients in cognitively impaired and non-impaired groups. The phenotype of MS was only Relapsing-remitting multiple sclerosis (RRMS) in 3 studies and in the other 10 studies, it was a mixture of RRMS, clinically isolated syndrome (CIS), and progressive MS. Most of the reports did not find a significant association between ApoE genotype and cognitive outcomes in patients with MS. Contrary to the expectations, patients in ApoE4- group were more likely to have impairment in Judgment of Line Orientation (JLO) (OR: 0.405; 95% CI: 0.173 to 0.949, p-value:0.038), while ApoE4+ patients had more rate of impairment in SRT (OR:1.901; 95%CI: 1.237 to 2.920; p-value:0.003). Appropriate identifying and dealing with cofounding factors were the most common source of bias in our included studies. CONCLUSION: ApoE may have a domain-specific association with cognitive impairment in MS patients. ApoE4 patients had more delayed responses to stimuli, but the rate of impaired visuospatial perception is lower in these patients. Based on the current evidence, there is a doubt about the clinical significance of this association.