Phytocannabinoids in neuromodulation: From omics to epigenetics.

BACKGROUND: Recent developments in metabolomics, transcriptomic and epigenetics open up new horizons regarding the pharmacological understanding of phytocannabinoids as neuromodulators in treating anxiety, depression, epilepsy, Alzheimer's, Parkinson's disease and autism. METHODS: The present review is an extensive search in public databases, such as Google Scholar, Scopus, the Web of Science, and PubMed, to collect all the literature about the neurobiological roles of cannabis extract, cannabidiol, 9-tetrahydrocannabinol specially focused on metabolomics, transcriptomic, epigenetic, mechanism of action, in different cell lines, induced animal models and clinical trials. We used bioinformatics, network pharmacology and enrichment analysis to understand the effect of phytocannabinoids in neuromodulation. RESULTS: Cannabidomics studies show wide variability of metabolites across different strains and varieties, which determine their medicinal and abusive usage, which is very important for its quality control and regulation. CB receptors interact with other compounds besides cannabidiol and Δ9-tetrahydrocannabinol, like cannabinol and Δ8-tetrahydrocannabinol. Phytocannabinoids interact with cannabinoid and non-cannabinoid receptors (GPCR, ion channels, and PPAR) to improve various neurodegenerative diseases. However, its abuse because of THC is also a problem found across different epigenetic and transcriptomic studies. Network enrichment analysis shows CNR1 expression in the brain and its interacting genes involve different pathways such as Rap1 signalling, dopaminergic synapse, and relaxin signalling. CBD protects against diseases like epilepsy, depression, and Parkinson's by modifying DNA and mitochondrial DNA in the hippocampus. Network pharmacology analysis of 8 phytocannabinoids revealed an interaction with 10 (out of 60) targets related to neurodegenerative diseases, with enrichment of ErbB and PI3K-Akt signalling pathways which helps in ameliorating neuro-inflammation in various neurodegenerative diseases. The effects of phytocannabinoids vary across sex, disease state, and age which suggests the importance of a personalized medicine approach for better success. CONCLUSIONS: Phytocannabinoids present a range of promising neuromodulatory effects. It holds promise if utilized in a strategic way towards personalized neuropsychiatric treatment. However, just like any drug irrational usage may lead to unforeseen negative effects. Exploring neuro-epigenetics and systems pharmacology of major and minor phytocannabinoid combinations can lead to success.

Genetic heterogeneity and respiratory chain enzyme analysis in pediatric Indian patients with mitochondrial disorder: Report of novel variants in POLG1 gene and their functional implication using molecular dynamic simulation.

Mitochondrial disorders are a heterogeneous group of disorders caused by mutations in the mitochondrial DNA or in nuclear genes encoding the mitochondrial proteins and subunits. Polymerase Gamma (POLG) is a nuclear gene and mutation in the POLG gene are one of the major causes of inherited mitochondrial disorders. In this study, 15 pediatric patients, with a wide spectrum of clinical phenotypes were screened using blood samples (n = 15) and muscle samples (n = 4). Respiratory chain enzyme analysis in the muscle samples revealed multi-complex deficiencies with Complex I deficiency present in (1/4) patients, Complex II (2/4), Complex III (3/4) and Complex IV (2/4) patients. Multiple large deletions were observed in 4/15 patients using LR-PCR. Whole exome sequencing (WES) revealed a compound heterozygous mutation consisting of a POLG1 novel variant (NP_002684.1:p.Trp261X) and a missense variant (NP_002684.1:p. Leu304Arg) in one patient and another patient harboring a novel homozygous POLG1 variant (NP_002684.1:p. Phe750Val). These variants (NP_002684.1:p. Leu304Arg) and (NP_002684.1:p. Phe750Val) and their interactions with DNA were modelled using molecular docking and molecular dynamics (MD) simulation studies. The protein conformation was analyzed as root mean square deviation (RMSD), root mean square fluctuation (RMSF) which showed local fluctuations in the mutants compared to the wildtype. However, Solvent Accessible Surface Area (SASA) significantly increased for NP_002684.1:p.Leu304Arg and decreased in NP_002684.1:p.Phe750Val mutants. Further, Contact Order analysis indicated that the Aromatic-sulfur interactions were destabilizing in the mutants. Overall, these in-silico analysis has revealed a destabilizing mutations suggesting pathogenic variants in POLG1 gene.