Renin-Angiotensin-Aldosterone System Inhibitors Prevent the Onset of Oxaliplatin-Induced Peripheral Neuropathy: A Retrospective Multicenter Study and in Vitro Evaluation.

Oxaliplatin (OXA) is used in chemotherapy for various cancer types and is associated with acute and chronic neurotoxicity. However, a preventive strategy for OXA-induced peripheral neuropathy (OIPN) and its underlying mechanism remain unclear. We examined the effects of renin-angiotensin-aldosterone system inhibitors (RAASIs) on OIPN by performing a retrospective multicenter study and an in vitro assay. We retrospectively evaluated electronic medical records of 976 patients who underwent one or more courses of OXA-containing regimens at Ehime, Okayama, and Tokushima University Hospitals. The primary endpoint was the incidence of OIPN during or after OXA administration. The effects of RAASIs and OXA on the neurite length in PC12 cells were determined. The combined administration of an OXA-containing regimen and RAASI significantly inhibited the cumulative incidence grade-2 or higher OIPN (log-rank test; p = 0.0001). RAASIs markedly suppressed the development of both acute and chronic OIPN (multivariate analysis; p = 0.017 and p = 0.011). In an in vitro assay, 10 µM OXA suppressed the neurite length; treatment with 1 µM aliskiren, spironolactone, 10 µM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1 µM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500 µM SQ22536 (a cell-permeable adenylate cyclase (AC) inhibitor) markedly abolished neurite-extending effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may increase in the activity of ERK1/2 and AC in PC12 cells.

Regulatory effects of nicotine on neurite outgrowth in rat superior cervical ganglia cells.

We have reported that nicotine has a neurotrophic action on peripheral adrenergic nerves in vivo, which is mediated by α7 nicotinic acetylcholine receptors (nAChRs). To clarify the possible mechanisms, the present study further investigated the effect of nicotine on neurite outgrowth in tyrosine hydroxylase (TH)-positive superior cervical ganglia (SCG) cells isolated from neonatal rats in vitro. Nicotine at low concentrations (0.01-0.3 mM) increased the number of neurite outgrowths in TH-immunopositive SCG cells, while high concentrations of nicotine (1-10 mM) gradually reduced it, and only 10 mM nicotine was markedly inhibited compared to the control. A 100 µM of nicotine-induced increase in neurite numbers depended on the exposure time and was inhibited by treatment with the nAChR antagonist hexamethonium (Hex) and α7 nAChR antagonist α-bungarotoxin (α-Bgtx). The nicotine (10 mM)-induced a significant decrease in neurite outgrowth in SCG, which was perfectly canceled by Hex to the control level but not by α-Bgtx. These results suggest that nicotine has a regulatory neurotrophic action mediated by both α7 nAChR and other subtypes in TH-positive SCG cells of rats.

Neurotrophic effect of hepatic growth factor (HGF) on reinnervation of perivascular calcitonin gene-related peptide (CGRP)-containing nerves following phenol-induced nerve injury in the rat mesenteric artery.

Hepatic growth factor (HGF) has neurotrophic effects in the motor neurons and central nervous system. However, there has been no report about the neurotrophic action on perivascular nerves innervating the resistance artery. We investigated whether HGF can restore innervation or function of perivascular nerves, including neuropeptide Y (NPY)-containing sympathetic adrenergic nerves and calcitonin gene-related peptide (CGRP)-containing nerves, in rat mesenteric artery. To investigate HGF-mediated neurotrophic effects, Wistar rats under pentobarbital-Na anesthesia underwent in vivo perivascular denervation by topical application of phenol on the superior mesenteric artery, and then HGF or nerve growth factor (NGF) was administered for 7 days using an osmotic mini-pump after phenol-treatment. HGF significantly increased the density and number of CGRP-like immunoreactivity (LI)-containing nerve fibers compared with saline administration, while HGF did not affect the density of NPY-containing adrenergic nerve fibers. After 7-day treatment with HGF and phenol, the vascular response of vasodilation was recovered from nerve injury by phenol treatment, but vasoconstriction was not. HGF and NGF induced neurite outgrowth in rat cultured dorsal root ganglia (DRG). These results suggest that HGF has a specific neurotrophic action on reinnervation of vascular CGRP-LI-containing nerve fibers in the rat mesenteric artery and DRG.

The 5-HT1A receptor full agonist, 8-OH-DPAT inhibits ACTH-induced 5-HT2A receptor hyperfunction in rats: involvement of 5-HT1A receptors in the DOI-induced wet-dog shakes in ACTH-treated rats.

We examined the influence of 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a serotonin 1A (5-HT1A) receptor full agonist, on the wet-dog shake response induced by the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, in adrenocorticotropic hormone (ACTH)-treated rats. Chronic ACTH (100 microg/rat, s.c.) treatment for 14 d increased the wet-dog shake response induced DOI. The 8-OH-DPAT inhibited the wet-dog shake response induced by DOI in rats with ACTH for 14 d. On the other hand, the 8-OH-DPAT-induced hypothermia and flat body posture were inhibited when ACTH was administered for 14 d. These findings suggest that chronic treatment with ACTH decreased the sensitivity of the 5-HT1A receptor system; however, the inhibitory effects from the 5-HT1A receptors to the 5-HT2A receptor system is not inhibited in ACTH-treated rats.