Wednesday, June 12, 2013

Silent Information Regulator 1 (SIRT1) and neuroprotection

Nandakumar Nagaraja, MD

Hernández-Jiménez M, Hurtado O, Cuartero MI, Ballesteros I, Moraga A, Pradillo JM. Silent Information Regulator 1 Protects the Brain Against Cerebral Ischemic Damage. Stroke. 2013


Silent Information Regulator 1 (SIRT1), also known as Sirtuin 1 is a NAD+ dependent protein deacetylase implicated in aging, neurodegeneration and ischemic preconditioning in the heart and brain.

In a recent article published in the journal Stroke, Hernandez-Jimenez and colleagues evaluated the role of SIRT1 in the mouse model of permanent MCA occlusion. The study showed that SIRT1 was found in the cytoplasm of neurons. Activation of SIRT1 resulted in decrease in infarct volume. Inhibition or genetic deletion of SIRT1 resulted in increase in infarct volume. They also found that SIRT1 played a role in inhibition of p53 and NFkB induced inflammatory and apoptotic pathways. Therapeutic agents that target SIRT1 and increase its activity could be potentially used for treatment of stroke to reduce the infarct volume.

Several neuroprotective agents that were shown to be effective in the laboratory have failed to show significant benefit in phase III clinical trials. In an effort to effectively translate preclinical studies into clinical trials the STAIR (Stroke Therapy Academic Industry Roundtable) committee has provided recommendations for the preclinical studies in the laboratory. Some of the recommendations include establishing efficacy in two or more laboratories, replication in a second species, studies involving females, aged animals and animals with co-morbid conditions such as hypertension, diabetes and hypercholesterolemia etc. In the next few years it would be interesting to watch out for such preclinical studies targeting SIRT1 modulation as a mechanism for neuroprotection in cerebral ischemia and also delineating the molecular cascade of events that result in neuroprotection.






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