NNZ-2566, a glypromate analog, attenuates brain ischemia-induced non-convulsive seizures in rats.

Abstract

Ischemic and traumatic brain injuries often induce non-convulsive seizures (NCSs), which likely contribute to the worsening of neurological outcomes. Here, we evaluated the effect of glycyl-L-methylprolyl-L-glutamic acid (NNZ-2566) to lessen the severity of NCSs caused by permanent middle cerebral artery occlusion (pMCAo). Continuous electroencephalographic recordings were performed in rats during pMCAo. Glycyl-L-methylprolyl-L-glutamic acid (3, 10, or 100 mg/kg bolus followed by an infusion of a fixed dose of 3 mg/kg per hour for 12 h) was delivered at 20 mins after pMCAo (before the first NCS event) or delayed until immediately after the first NCS event occurred. Control rats received pMCAo and saline treatment. The results revealed that 91% of the saline-treated animals had NCSs (23 episodes per rat and 1238 secs per rat) with an onset latency of 35 mins after injury. When NNZ-2566 was administered before the NCS events, it dose-dependently reduced the NCS incidence to 36%-80%, decreased NCS frequency to 5-16 episodes per rat, and shortened the total duration of NCS to 251-706 secs per rat. The two high doses significantly reduced the infarct volume by 28%-30%. Delayed treatment also attenuated NCS duration but had no effect on the infarct volume. Results indicate that NNZ-2566 possesses a unique therapeutic potential as a safe prophylactic agent that synergistically provides neuroprotection and reduces injury-induced seizures.

• Authors: Xi-Chun M Lu, Yuanzheng Si, Anthony J Williams, Jed A Hartings, Divina Gryder, Frank C Tortella
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 29 Issue 12 Pg. 1924-32 (Dec 2009) ISSN: 1559-7016 [Electronic] United States
• PMID: 19638995 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• NNZ 2566
• Neuroprotective Agents
• Oligopeptides
• glycyl-prolyl-glutamic acid

Topics

• Animals
• Brain Infarction (drug therapy)
• Brain Ischemia (complications)
• Electroencephalography
• Male
• Neuroprotective Agents (therapeutic use)
• Oligopeptides (chemistry, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Seizures (drug therapy, etiology)