Fluvastatin Sodium

Epilepsy affects nearly 50 million people worldwide. Previous studies have indicated the neuroprotective effects of statin on several neuropathological conditions. However, it is very much unknown whether fluvastatin was able to alter the seizure types related to neuronal excitability and progression mediated by NMDA receptor activation, and the mechanisms involved in these actions are not completely understood so far. Our study evaluated the effects of fluvastatin on the NMDA-induced seizure, BK_Ca channels activity, NMDA receptor activation opens BK_Ca current, sodium channel current, NMDA receptor-mediated current, and hyperexcitable neuronal activity associated with activation of NMDA receptor.

The effects of fluvastatin on seizure thresholds induced by NMDA were monitored in mice. The cell-attached and whole-cell patch-clamp recordings were applied to evaluate the ionic currents and action potentials of rCN or SHSY5Y neuroblastoma cells.

The results of our study have demonstrated that fluvastatin did increase the NMDA-induced seizure threshold and suppressed the frequency of action potentials induced by NMDA. Notably, our findings provide the evidence that fluvastatin exhibits inhibitory effects on NMDA receptor-mediated current, BK_Ca channels currents, NMDA receptor activation opens BK_Ca current, and sodium channel currents in rCN and SHSY5Y neuroblastoma cells.

Our findings suggested that fluvastatin may protect against seizure types related to neuronal excitability and NMDA receptor activation by inhibiting NMDA-mediated action potentials, NMDA receptor-mediated currents, BK_Ca channels, and sodium channels.

Cholesterol plays pivotal cellular functions ranging from maintaining membrane fluidity to regulating cell-cell signaling. High cholesterol causes cardiovascular diseases, low cholesterol is linked to neuropsychiatric disorders, and inborn errors of cholesterol synthesis cause multisystem malformation syndromes. Statins lower cholesterol levels by inhibiting the first, rate-limiting reaction of the cholesterol biosynthesis pathway catalyzed by hydroxymethyl-glutaryl-Coenzyme A reductase (HMGCR). However, they have also been shown to interfere with cellular pathways that are unrelated to cholesterol synthesis. One of the last enzymes of cholesterol biosynthesis, 7-dehydrocholesterol reductase (DHCR7), is often mutated in the Smith-Lemli-Opitz syndrome (SLOS), a multisystem malformation syndrome. Strikingly, recent studies have shown that some prescribed psychotropic pharmaceuticals inhibit its activity. In this study, we used Xenopus laevis as a model organism to test the effects of 8 FDA-approved statins and selected prescribed psychotropic drugs on the developing vertebrate embryo. Drugs were tested at concentrations ranging from 0.1 µM to 50 µM. Embryos were exposed to the drugs from the blastula stage through the swimming tadpole stage with daily medium change. Our data show that statins are heterogenous with respect to their ability to cause embryonic lethality, with simvastatin, pitavastatin, lovastatin, cerivastatin, and fluvastatin being the most toxic ones. Observed phenotypes included delayed development, shortened body axis and pericardiac edema. On the other hand, psychotropic drugs were less embryonic lethal than statins but caused similar phenotypes as well as microcephaly and holoprosencephaly. Our findings suggest that the proximal and distal inhibition of cholesterol biosynthesis have different but overlapping effects on embryonic development.