Chronic BZD Perturbs Mitochondrial Membrane Proteins and Provokes the Aging Like Effect on Motoric Function

Purpose: Benzodiazepines (BZDs) are CNS depressants and are among the most commonly prescribed medications to treat hyperexcitatory disorders such as insomnia. However, its high or a repeated dose is frequently administered to patients who are resistant to the therapeutic effects of BZD. A high or a repeated dose of BZD often provokes side effects including respiratory suppression and motoric impairment which can be more severe in elderly than young persons. Here, we investigated the adverse effects of BZD (lorazepam) on the integrity of mitochondria in the brain of mice. Methods: Young adult male mice were injected with BZD (1 mg/kg) for 14 days and tested for motoric function using Rotarod. Older mice (12 months old) were injected with a vehicle for 14 days and tested for Rotarod test. Mice were then euthanized to collect a whole brain. The expression of mitochondrial membrane proteins such as mitochondrial (peripheral) benzodiazepine receptor (PBR), mitochondrial creatin kinase (mCK), and cytochrome c oxidase (COX) was measured in the prefrontal cortex using the immunoblot method. Results: Compared to young control mice, young mice injected with chronic BZD showed poorer Rotarod performance by more quickly falling from Rotarod. The latency to fall from Rotarod of younger BZD mice (3 months old) was as short as that of older control mice (12 months old). Young mice injected with chronic BZD showed an increase in the expression of PBR and COX and a decrease in mCK. Conclusions: These data suggest that a chronic dose of BZD can facilitate the aging process through damaging the integrity of mitochondrial membranes. Supported by NIH/AA018747.