Distribution and functional characterization of pituitary adenylate cyclase-activating polypeptide receptors in the brain of non-human primates.

V. Jolivel (1, 2, 3) , M. Basille (1, 3) , N. Aubert (1, 3, 4) , S. de Jouffrey (4) , P. Ancian (4) , J.-F. Le Bigot (4) , P. Noack (2) , M. Massonneau (2) , A. Fournier (3, 5) , H. Vaudry (1, 3) , B. J. Gonzalez (1, 3) , D. Vaudry (1, 3)

1 Neuroendocrinologie cellulaire et moléculaire
2 QUIDD - Quantitative Imaging in Drug Development
3 International Associated laboratory Samuel de Champlain
4 CIT - Centre International de Toxicologie
5 INRS-IAF - Institut Armand Frappier

The distribution and density of pituitary adenylate cyclase-activating polypeptide (PACAP) binding sites have been investigated in the brain of the primates Jacchus callithrix (marmoset) and Macaca fascicularis (macaque) using [(125)I]-PACAP27 as a radioligand. PACAP binding sites were widely expressed in the brain of these two species with particularly high densities in the septum, hypothalamus and habenula. A moderate density of recognition sites was seen in all subdivisions of the cerebral cortex with a heterogenous distribution, the highest concentrations occurring in layers I and VI while the underlying white matter was almost devoid of binding sites. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed intense expression of the mRNAs encoding the short and hop-1 variants of pituitary adenylate cyclase-activating polypeptide-specific receptor (PAC1-R) in the cortex of both marmoset and macaque, whereas vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating polypeptide mutual receptor, subtype 1 (VPAC1-R) and vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating polypeptide mutual receptor, subtype 2 (VPAC2-R) mRNAs were expressed at a much lower level. In situ hybridization histochemistry showed intense expression of PAC1-R and weak expression of VPAC1-R mRNAs in layer IV of the cerebral cortex. Incubation of cortical tissue slices with PACAP induced a dose-dependent stimulation of cyclic AMP formation, indicating that PACAP binding sites correspond to functional receptors. Moreover, treatment of primate cortical slices with 100 nM PACAP significantly reduced the activity of caspase-3, a key enzyme of the apoptotic cascade. The present results indicate that PACAP should exert the same neuroprotective effect in the brain of primates as in rodents and suggest that PAC1-R agonists may have a therapeutic value to prevent neuronal cell death after stroke or in specific neurodegenerative diseases.

Domaines: Toxicologie

V. Jolivel, M. Basille, N. Aubert, S. de Jouffrey, P. Ancian, et al.. Distribution and functional characterization of pituitary adenylate cyclase-activating polypeptide receptors in the brain of non-human primates.. Neuroscience, 2009, 160 (2), pp.434-51. ⟨10.1016/j.neuroscience.2009.02.028⟩. ⟨pasteur-00819922⟩