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α7 nicotinic acetylcholine receptor agonist PNU-282987 attenuates early brain injury in a perforation model of subarachnoid hemorrhage in rats.

AbstractBACKGROUND AND PURPOSE:
Early brain injury is an important pathological process after subarachnoid hemorrhage (SAH). The goal of this study was to evaluate whether the α7 nicotinic acetylcholine receptor (α7nAChR) agonist PNU-282987 attenuates early brain injury after SAH and whether α7nAChR stimulation is associated with down-regulation of caspase activity via phosphatidylinositol 3-kinase-Akt signaling.
METHODS:
The perforation model of SAH was performed, and neurological score, body weight loss, and brain water content were evaluated 24 and 72 hours after surgery. Western blot and immunohistochemistry were used for quantification and localization of phosphorylated Akt and cleaved caspase 3. Neuronal cell death was quantified with TUNEL staining. α7nAChR antagonist methylcaconitine and phosphatidylinositol 3-kinase inhibitor wortmannin were used to manipulate the proposed pathway, and results were quantified with Western blot.
RESULTS:
PNU-282987 improved neurological deficits both 24 and 72 hours after surgery and reduced brain water content in left hemispheres 24 hours after surgery. PNU-282987 significantly increased phosphorylated Akt levels and significantly decreased cleaved caspase 3 levels in ipsilateral hemispheres after SAH. Methylcaconitine and wortmannin reversed effects of treatment. Phosphorylated Akt and cleaved caspase 3 were colocalized to neurons in the ipsilateral basal cortex. Phosphorylated Akt was mainly localized in TUNEL-negative cells. PNU-282987 significantly reduced neuronal cell death in the ipsilateral basal cortex.
CONCLUSIONS:
α7nAChR stimulation decreased neuronal cell death and brain edema and improved neurological status in a rat perforation model of SAH. α7nAChR stimulation is associated with increasing phosphorylation of Akt and decreasing cleaved caspase 3 levels in neurons.
AuthorsKamil Duris, Anatol Manaenko, Hidenori Suzuki, William B Rolland, Paul R Krafft, John H Zhang
JournalStroke (Stroke) Vol. 42 Issue 12 Pg. 3530-6 (Dec 2011) ISSN: 1524-4628 [Electronic] United States
PMID21960575 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Benzamides
  • Bridged Bicyclo Compounds
  • Nicotinic Agonists
  • PNU-282987
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
Topics
  • Animals
  • Apoptosis (drug effects)
  • Benzamides (pharmacology, therapeutic use)
  • Blood Pressure (drug effects)
  • Brain Injuries (drug therapy, metabolism, pathology)
  • Bridged Bicyclo Compounds (pharmacology, therapeutic use)
  • Caspase 3 (metabolism)
  • Disease Models, Animal
  • Heart Rate (drug effects)
  • Male
  • Neurons (drug effects, metabolism, pathology)
  • Nicotinic Agonists (pharmacology, therapeutic use)
  • Phosphorylation (drug effects)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Subarachnoid Hemorrhage (drug therapy, metabolism, pathology)

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