Multimodal neuroprotection induced by PACAP38 in oxygen-glucose deprivation and middle cerebral artery occlusion stroke models.
Pituitary adenylate cyclase activating peptide (PACAP), a potent neuropeptide which crosses the blood-brain barrier, is known to provide neuroprotection in rat stroke models of middle cerebral artery occlusion (MCAO) by mechanism(s) which deserve clarification. We confirmed that following i.v. injection of 30 ng/kg of PACAP38 in rats exposed to 2 h of MCAO focal cerebral ischemia and 48 h reoxygenation, 50 % neuroprotection was measured by reduced caspase-3 activity and volume of cerebral infarction. Similar neuroprotective effects were measured upon PACAP38 treatment of oxygen-glucose deprivation and reoxygenation of brain cortical neurons. The neuroprotection was temporally associated with increased expression of brain-derived neurotrophic factor, phosphorylation of its receptor-tropomyosin-related kinase receptor type B (trkB), activation of phosphoinositide 3-kinase and Akt, and reduction of extracellular signal-regulated kinases 1/2 phosphorylation. PACAP38 increased expression of neuronal markers beta-tubulin III, microtubule-associated protein-2, and growth-associated protein-43. PACAP38 induced stimulation of Rac and suppression of Rho GTPase activities. PACAP38 downregulated the nerve growth factor receptor (p75(NTR)) and associated Nogo-(Neurite outgrowth-A) receptor. Collectively, these in vitro and in vivo results propose that PACAP exhibits neuroprotective effects in cerebral ischemia by three mechanisms: a direct one, mediated by PACAP receptors, and two indirect, induced by neurotrophin release, activation of the trkB receptors and attenuation of neuronal growth inhibitory signaling molecules p75(NTR) and Nogo receptor.
School of Pharmacy Institute for Drug Research, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. philipl@ekmd.huji.ac.il
Philip
P
Lazarovici
Gadi
G
Cohen
Hadar
H
Arien-Zakay
Jieli
J
Chen
Chunling
C
Zhang
Michael
M
Chopp
Hao
H
Jiang
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007275:Injections, Intravenous; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D005947:Glucose