okadaic-acid and Infarction--Middle-Cerebral-Artery

Ca(2+) influxes are regulated by the functional state of N-methyl-D-aspartate receptors (NMDARs). Dephosphorylation of NMDARs subunits decreases Ca(2+) influxes. NR3, a novel subunit of NMDARs, also decreases Ca(2+) influxes by forming new NMDARs with NR1 and NR2. It is meaningful to uncover whether protein phosphatase 2A (PP2A) and NR3A play a role in the protective effect of Simvastatin on ischemic stroke. In the present study, the Sprague-Dawley rats were pretreated with Simvastatin for 7 days before middle cerebral artery occlusion was performed to mimic ischemic stroke. The results showed that Simvastatin decreased brain ischemic infarct area significantly while increasing the expression levels of PP2A and NR3A, thus dephosphorylating the serine sites of NR1 (ser896 and ser897) along with increased enzymatic activities of PP2A. The protein levels of NR3A decreased as the enzymatic activities of PP2A were inhibited by okadaic acid. The results indicated that Simvastatin could protect the cerebrum from ischemic injury through a signaling mechanism involving elevated levels of PP2A and NR3A, and that PP2A might involve in the regulatory mechanism of NR3A expression.

Topics: Animals; Brain Ischemia; CA1 Region, Hippocampal; Gene Expression Regulation; Genetic Pleiotropy; Infarction, Middle Cerebral Artery; Male; Okadaic Acid; Phosphorylation; Protein Phosphatase 2; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Simvastatin; Stroke; Up-Regulation

The N-terminal cleavage product of human insulin-like growth factor-1 (IGF-1) in the brain is the tripeptide molecule Glypromate (Gly-Pro-Glu). Glypromate has demonstrated neuroprotective effects in numerous in vitro and in vivo models of brain injury and is in clinical trials for the prevention of cognitive impairment following cardiac surgery. NNZ-2566 is a structural analogue of Glypromate, resulting from alpha-methylation of the proline moiety, which has improved the elimination half-life and oral bioavailability over the parent peptide. In vivo, NNZ-2566 reduces injury size in rats subjected to focal stroke. An intravenous infusion of NNZ-2566 of 4 h duration (3-10 mg/kg/h), initiated 3 h after endothelin-induced middle-cerebral artery constriction, significantly reduced infarct area as assessed on day 5. Neuroprotective efficacy in the MCAO model was also observed following oral administration of the drug (30-60 mg/kg), when formulated as a microemulsion. In vitro, NNZ-2566 significantly attenuates apoptotic cell death in primary striatal cultures, suggesting attenuation of apoptosis is one mechanism of action underlying its neuroprotective effects. NNZ-2566 is currently in clinical trials for the treatment of cognitive deficits following traumatic brain injury, and these data further support the development of the drug as a neuroprotective agent for acute brain injury.

Topics: Administration, Oral; Animals; Apoptosis; Blood Chemical Analysis; Brain; Disease Models, Animal; Female; Infarction, Middle Cerebral Artery; Infusions, Intravenous; Male; Microdialysis; Neuroprotective Agents; Okadaic Acid; Oligopeptides; Rats; Rats, Sprague-Dawley; Stroke