4-oxo-6-((pyrimidin-2-ylthio)methyl)-4h-pyran-3-yl-4-nitrobenzoate and Disease-Models--Animal

Apelin is hypothesized to serve a dual function in pain processing. Spinal administration of apelin induces hyperalgesia, while opioid receptors are implicated in the antinociceptive effects of apelin in acute nociceptive models. However, whether the apelin‑apelin receptor (APJ) system is involved in neuropathic pain remains to be elucidated. The present study aimed to evaluate the impact and mechanism of the spinal apelin‑APJ system in neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve produced sustained spinal apelin and APJ upregulation, which was associated with mechanical allodynia and heat hyperalgesia development in the hind‑paw plantar surface. Immunofluorescence demonstrated that apelin and APJ were localized to the superficial dorsal horns. In order to further clarify the function of the apelin‑APJ system, a single intrathecal administration of ML221, an APJ antagonist, was used; this transiently reduced CCI‑induced pain hypersensitivity. However, apelin‑13 (the isoform which binds most strongly to APJ) exhibited no effect on the nociceptive response, suggesting an essential role for the spinal apelin‑APJ system in neuropathic pain sensitization. The present study demonstrated that a single application of ML221 alleviated mechanical allodynia and heat hyperalgesia 7 days following CCI, in a dose‑dependent manner. Intraspinal delivery of ML221, at the onset of and in fully‑established neuropathic pain, persistently attenuated CCI‑induced pain hypersensitivity, indicating that the apelin‑APJ system was involved in initiating and maintaining pain. It was demonstrated, using immunoblotting, that intrathecal ML221 downregulated phosphorylated extracellular signal‑related kinase (ERK) in the rat spinal cord dorsal horn, suggesting that the effect of apelin on neuropathic pain may be mediated via ERK signaling. The results of the present study suggested that the spinal apelin‑APJ system may drive neuropathic pain. Inhibition of APJ may provide novel pharmacological interventions for neuropathic pain.

Topics: Animals; Apelin; Apelin Receptors; Chronic Disease; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Injections, Spinal; Male; Neuralgia; Nitrobenzoates; Peripheral Nerve Injuries; Phosphorylation; Pyrans; Rats; RNA, Messenger; Sciatic Nerve; Spinal Cord; Spinal Cord Dorsal Horn

Pathological retinal angiogenesis is caused by the progression of ischemic retinal diseases and can result in retinal detachment and irreversible blindness. This neovascularization is initiated from the retinal veins and their associated capillaries and involves the overgrowth of vascular endothelial cells. Since expression of the apelin receptor (APJ) is restricted to the veins and proliferative endothelial cells during physiological retinal angiogenesis, in the present study, we investigated the effect of APJ inhibition on pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). In vitro experiments revealed that ML221, an APJ antagonist, suppressed cultured-endothelial cell proliferation in a dose-dependent manner. Intraperitoneal administration of ML221 inhibited pathological angiogenesis but enhanced the recovery of normal vessels into the ischemic regions in the retina of the OIR model mice. ML221 did not affect the expression levels of vascular endothelial growth factor (VEGF) and its receptor (VEGFR2) in the retina. APJ was highly expressed in the endothelial cells within abnormal vessels but was only detected in small amounts in morphologically normal vessels. These results suggest that APJ inhibitors selectively prevent pathological retinal angiogenesis and that the drugs targeting APJ may be new a candidate for treating ischemic retinopathy.

Topics: Animals; Apelin; Apelin Receptors; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Gene Expression; Ischemia; Mice; Nitrobenzoates; Pyrans; Retinal Diseases; Retinal Neovascularization; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2