Validation of a therapeutic strategy involving the mitochondrial delivery of thiamine pyrophosphate using brain damage induced mouse model

Abstract

Ischemic brain disease, a type of cerebrovascular disease, has a high mortality rate, and even when patients survive, they are frequently affected by neurological dysfunction due to damage to brain cells. Strategies to increase intracellular adenosine triphosphate (ATP) production are promising approaches for tissue regeneration and restoring neurological function. We report here on an attempt to deliver thiamine pyrophosphate (TPP), a coenzyme that activates the tricarboxylic acid cycle, which is responsible for ATP production, to mitochondria. To achieve this, we used a MITO‐Porter, a liposomal drug delivery system for delivering various cargoes to mitochondria via membrane fusion. In the present study, we investigated the therapeutic effect of the MITO‐Porter (TPP) focusing on its delivery to the brain and neurological function using a bilateral common carotid artery occlusion (BCCAO) mouse model. Fluorescent microscopic analyses confirmed, after a cerebral ischemia‐reperfusion injury had been induced, that the intracerebral delivery of the MITO‐Porter occurred after intravenous administration. Behavioral analyses indicated that the MITO‐Porter (TPP) resulted in significant therapeutic effects compared to the corresponding administration of naked TPP. Histological evaluations also confirmed that the MITO‐Porter (TPP) clearly had an effect on the growth of brain neurons in the BCCAO mouse. Our findings indicate that the mitochondrial delivery of TPP represents a potential innovative therapeutic strategy for enhancing mitochondrial energy production in certain cases of brain diseases.

Development of a Mitochondrial Targeting Lipid Nanoparticle Encapsulating Berberine

“…The use of the R8-MITO-Porter (BBR) is expected to lead to enhanced pharmacological actions by inducing a more effective mitochondrial stress response. Previously, we have shown the successful delivery of cationic LNPs (R8-MITO-Porter) to the brain [ 27 ]. Moreover, treatment with cationic NPs that contain encapsulated BBR has been reported to improve learning and memory function at lower doses than treatment with naked BBR [ 28 ].…”