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Journal of Molecular Neuroscience

, Volume 48, Issue 3, pp 526–540 | Cite as

Multimodal Neuroprotection Induced by PACAP38 in Oxygen–Glucose Deprivation and Middle Cerebral Artery Occlusion Stroke Models

  • Philip LazaroviciEmail author
  • Gadi Cohen
  • Hadar Arien-Zakay
  • Jieli Chen
  • Chunling Zhang
  • Michael Chopp
  • Hao Jiang
Article

Abstract

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 (p75NTR) 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 p75NTR and Nogo receptor.

Keywords

Stroke Apoptosis Neuroprotection PACAP BDNF trkB p75 NgR Akt Erk1/2 

Abbreviations

Akt

PKB protein kinase B

Bax

Member of the pro-apoptotic Bcl-2 protein family

BDNF

Brain-derived neurotrophic factor

Erk1/2

Extracellular signal-regulated kinases 1/2

GAP-43

Growth-associated protein-43

LDH

Lactate dehydrogenase

MAP-2

Microtubule-associated protein-2

MCAO

Middle cerebral artery occlusion

NgR

Nogo receptor (inhibitor of neurite outgrowth Nogo 66)

OGD

Oxygen–glucose deprivation

p75NTR

Nerve growth factor receptor

PAC1

Pituitary adenylate cyclase receptor type 1

PACAP

Pituitary adenylate cyclase activating peptide

PI3-K

Phosphoinositide 3-kinase

Rac1

Ras-related C3 botulinum toxin substrate 1

RhoA

Ras homolog gene family member A

Rho-GDI

Rho GDP dissociation inhibitor

trkB

Tropomyosin-related kinase receptor type B

TuJ1

Neuron-specific class III beta-tubulin

Notes

Acknowledgments

PL holds the Jacob Gitlin Chair in Physiology and is affiliated and supported by David R. Bloom Center for Pharmacy and Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at the Hebrew University of Jerusalem, Israel. This work was also supported in part by NIH grants PO1 NS023393 (MC) and RO1 AG037506 (MC). The authors wish to thank Ms. Zehava Cohen for graphic work.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Philip Lazarovici
    • 1
    Email author
  • Gadi Cohen
    • 1
  • Hadar Arien-Zakay
    • 1
  • Jieli Chen
    • 2
  • Chunling Zhang
    • 2
  • Michael Chopp
    • 2
  • Hao Jiang
    • 2
  1. 1.School of Pharmacy Institute for Drug Research, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
  2. 2.Department of NeurologyHenry Ford Health Sciences CenterDetroitUSA

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