TY - JOUR T1 - The Akt-nitric oxide-cGMP pathway contributes to nerve growth factor-mediated neurite outgrowth in apolipoprotein E knockout mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.181487 SP - jpet.111.181487 AU - Narumi Hashikawa-Hobara AU - Naoya Hashikawa AU - Chikao Yutani AU - Yoshito Zamami AU - Xin Jin AU - Shingo Takatori AU - Mitsunobu Mio AU - Hiromu Kawasaki Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/05/18/jpet.111.181487.abstract N2 - Apolipoprotein E deficient (apoE-/-) mice have peripheral sensory nerve defects, and a reduced and delayed response to noxious thermal stimuli. However, to date, no report has focused on the influence of apoE deficiency on calcitonin gene-related peptide (CGRP)-containing nerve fiber extensions. We have shown that the density of CGRP containing nerve fibers decreases in mesenteric arteries of apoE-/- mice when compared to wild-type mice. Here, we investigated whether apoE deficiency is involved in nerve growth factor (NGF)-induced CGRP containing nerve regeneration using apoE-/- mice. NGF-mediated CGRP-like immunoreactivity (LI)-neurite outgrowth in apoE-/- cultured dorsal root ganglia (DRG) cells was significantly lower than wild-type cultures. However, the level of NGF receptor mRNA in apoE-/- DRG cells was similar to wild-type mice. To clarify the mechanism of the impaired ability of NGF-mediated neurite outgrowth, we focused on the Akt-NO-cGMP pathway. Expression of phosphorylated Akt was significantly reduced in apoE-/- DRG. The NO donor, sodium nitroprusside or S-nitroso-N-acetylpenicillamine, did not affect NGF-mediated neurite outgrowth in apoE-/- cultured DRG cells. However, 8-Bromoguanosine 3', 5'-cyclic monophosphate sodium salt n-hydrate (8-Br-cGMP), a cGMP analog, induced NGF-mediated nerve facilitation similar to wild-type NGF-mediated neurite outgrowth levels. Furthermore, in apoE-/- DRG, soluble guanylate cyclase expression was significantly lower than wild-type DRG. These results suggest that in apoE-/- mice the Akt-NO-cGMP pathway is impaired, which may be caused by NGF-mediated CGRP-LI-neurite outgrowth defects. ER -