Mitochondrial dysfunctions generating from
cerebral ischemia-reperfusion exert a potential threat on neuronal cell survival and hence, accelerate the aging process and age dependent neuropathology. Thirty min moderate
cerebral ischemia induced by bilateral common carotid artery occlusion (BCCAO) followed by 30 min reperfusion caused an increased diene production, depleted
glutathione (GSH) content, reduced
superoxide dismutase (SOD) and
catalase activities and pyramidal neuronal loss in young (2 months old) and aged (20 months old) rat brain compared to
sham operated controls.
Cytidine 5' diphosphocholine (
CDP-Choline) is a known
neuroprotective drug.
CDP-Choline after metabolism in the liver suffers hydrolysis and splits into
cytidine and
choline before entering systemic circulation and hardly circumvents blood brain barrier (BBB) as such. Previous reports show
CDP-Choline liposomes significantly increased in vivo uptake compared to "free
drug" administration in
cerebral ischemia. To enhance the therapeutic concentration build up in brain we sought to formulate mannosylated liposomal
CDP-Choline (MLCDP) utilizing the
mannose receptors. We tested the therapeutic supremacy of MLCDP over liposomal
CDP-Choline (LCDP) in global moderate
cerebral ischemia reperfusion induced neuronal damage.
CDP-Choline in MLCDP delivery system was found potent to exert substantial protection against global moderate
cerebral ischemia reperfusion induced mitochondrial damage in aged rat brain.
Membrane lipid peroxidation,
GSSG/GSH ratio and
reactive oxygen species (ROS) generation in cerebral tissue were found to be higher in aged, compared to young rat. Further decline of those parameters was observed in aged rat brain by the induction of global moderate
cerebral ischemia and reperfusion. MLCDP treatment when compared to free or LCDP treatment prevented global moderate
cerebral ischemia-reperfusion induced mitochondrial damage as evident ultra structurally and release of
cytochrome c (cyt c) from mitochondria into cytosol and protected mitochondria to restore its normal structure and functions.