PT  - JOURNAL ARTICLE
AU  - Hashikawa-Hobara, Narumi
AU  - Hashikawa, Naoya
AU  - Yutani, Chikao
AU  - Zamami, Yoshito
AU  - Jin, Xin
AU  - Takatori, Shingo
AU  - Mio, Mitsunobu
AU  - Kawasaki, Hiromu
TI  - The Akt-Nitric Oxide-cGMP Pathway Contributes to Nerve Growth Factor-Mediated Neurite Outgrowth in Apolipoprotein E Knockout Mice
AID  - 10.1124/jpet.111.181487
DP  - 2011 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 694--700
VI  - 338
IP  - 2
4099  - http://jpet.aspetjournals.org/content/338/2/694.short
4100  - http://jpet.aspetjournals.org/content/338/2/694.full
SO  - J Pharmacol Exp Ther2011 Aug 01; 338
AB  - Apolipoprotein E (apo)-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 compared with 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 that in wild-type cultures. However, the level of NGF receptor mRNA in apoE(−/−) DRG cells was similar to that in wild-type mice. To clarify the mechanism of the impaired ability of NGF-mediated neurite outgrowth, we focused on the Akt-nitric oxide (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, 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 that in 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.