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

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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.

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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

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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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Authors and Affiliations

  1. School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, POB 12065, Jerusalem, 91120, Israel

    Philip Lazarovici, Gadi Cohen & Hadar Arien-Zakay

  2. Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI, 48202, USA

    Jieli Chen, Chunling Zhang, Michael Chopp & Hao Jiang

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  1. Philip Lazarovici
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  2. Gadi Cohen
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  3. Hadar Arien-Zakay
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  7. Hao Jiang
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Correspondence to Philip Lazarovici.

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Lazarovici, P., Cohen, G., Arien-Zakay, H. et al. Multimodal Neuroprotection Induced by PACAP38 in Oxygen–Glucose Deprivation and Middle Cerebral Artery Occlusion Stroke Models. J Mol Neurosci 48, 526–540 (2012). https://doi.org/10.1007/s12031-012-9818-1

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