Ischemic cerebrovascular disease, IVCD, has high morbidity, mortality and disability rates and occupies 70~80% of all the cerebral blood diseases. It is the first cause of disability and the third leading cause of death worldwide.
Many studies show that ischemic brain damage results from multiple factors such as changes of neurotransmitters, tissue acidosis, production of free radicals, ion imbalance, lipid peroxidation, apoptosis and Inflammation. Drug treatment is one of the most important therapeutic methods of ischemic diseases.
At present thrombolytics, a scavenger of free radicals, GABA-ergic drugs and calcium channel blockers have been used in the treatment of IVCD.
On the basis of the complexity of the pathogenesis in cerebral ischemia and the disappointing results from single agent trials, it may be unrealistic to expect that a single neuroprotective drug will demonstrate benefit and effective therapy will require a combinational approach.
We conducted researches for the therapeutic and preventive use of ALCAR (acetyl-L-carnitine) on the ischemic brain damage by discovering it's neuroprotective effect, which is made by the department of biological chemistry,
Acetyl-L-carnitine (ALCAR) is an endogenous compound present in the central nervous system. It is the acetyl ester of L-carnitine, biosynthesized by the acetylation of carnitine through carnitine acetyltransferase.
ALCAR has an important role in the transport of long chain fatty acid into mitochondria. Many investigators have tried to seek for the role of acetylcarnitine, and found the improvement of performance in spatial learning tasks in aged rats, the enhancement on rat brain energy and phospholipid metabolism, the prolongation on the survival of adult rat sensory neurons and the anti-amnesic effect and the inhibitory effect on apoptosis. Furthermore, the progression of Alzheimer's disease has been significantly reduced in patients who had received acetyl carnitine.
The pharmacological effects of ALCAR may be due to its ability to induce energy metabolism and to modulate several neurotransmitter functions. It has been reported that ALCAR donates the acetyl groups to the TCA cycle, besides reducing the cerebral lactate levels. In addition, ALCAR has the ability to modulate the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, nerve growth factor (NGF) receptors and glucocorticoid receptors in aged animals.
ALCAR is supposed to have anti-oxidative property from data that it normalized the mitochondrial functions and reduced the content of serum cholesterol and lipid peroxides of the brain.
From these data, we supposed that acetyl-L-carnitine could be effective on ischemia-reperfusion injury of the brain and tried to reveal its neuroprotective effects.
ALCAR was administered at a dose of 200, 400, 600, 800mg/kg once a day, p.o. in the rats for 7 days. At 30 min after last administration, the middle cerebral artery was occluded by the thread advancement. The ischemia-reperfusion model was produced by the withdrawal of a thread at 90 min after MCAO.
We evaluated the effects of ALCAR on the ischemia-reperfusion injury at 24h after reperfusion.
First, we evaluated the effect of ALCAR on the neurological deficit caused by cerebral ischemia-reperfusion in the animal model. It decreased significantly neurological deficit compared with the model at a dose of >400mg. (p<0.05, p<0.01) And there is no significant difference between ALCAR and nimodipine group(40mg/kg).
Then the brain was removed and refrigerated at -20℃ and cut into 2mm thick slices. The slices were stained with 2% TTC solution and were photographed by digital camera and analyzed by Motic images plus 2.0, image-analyzing program.
We found that ALCAR reduced infarction area significantly and water content of the brain at a dose of >400mg and shows no obvious difference compared with nimodipine group (40mg/kg). (p<0.05, p<0.01)
We observed the effects of ALCAR on the certain biochemical indices to clarify the mechanism of it's protective action on the cerebral ischemia-reperfusion injury. We prepared the 10% homogenate and measured the SOD activity(nitrite method) and MDA content(thiobarbiturate method). As a result, the drug group shows significant increase of SOD activity and significant decrease of MDA content compared with model group.(p<0.05)
From these results, we found that ALCAR has a protective effect on local cerebral ischemia-reperfusion injury and are going to prove it's effectiveness in the clinical practice in the future.
At the same time we hope to collaborate in the research with related investigators who are interested in our study.
