NPY Receptor 2 Mediates NPY Antidepressant Effect in the mPFC of LPS Rat by Suppressing NLRP3 Signaling Pathway

Abstract

Accumulated evidences show that neuroinflammation play a pivotal role in the pathogenesis of depression. Neuropeptide Y (NPY) and its receptors have been demonstrated to have anti-inflammative as well as antidepressant effects. In the present study, the ability of NPY to modulate depressive-like behaviors induced by lipopolysaccharides (LPS) in rats and the receptors and signaling mechanisms involved were investigated. Continuous injection LPS (i.p) for 4 days led to development of depressive-like behaviors in rats, accompanied with M1-type microglia activation and increased levels of IL-1β as well as decreased levels of NPY and Y2R expression in the mPFC selectively. Local injection of NPY into the medial prefrontal cortex (mPFC) ameliorated the depression-like behaviors and suppressed the NLRP3 inflammasome signaling pathway. Y2R agonist PYY (3-36) mimicked and Y2R antagonist BIIE0246 abolished the NPY effects in the mPFC. All these results suggest that NPY and Y2R in the mPFC are involved in the pathophysiology of depression and NPY plays an antidepressant role in the mPFC mainly via Y2R, which suppresses the NLRP3 signaling pathway, in LPS-induced depression model rats.

RETRACTED ARTICLE: HDAC1-Mediated MicroRNA-124-5p Regulates NPY to Affect Learning and Memory Abilities in Rats with Depression

“…NPY was down-regulated in depressed rats and up-regulation of NPY promoted learning and memory ability recovery in depressed rats. In the development of depressive-like behaviors, the rat models are manifested with reduced NPY expression [ 17 ]. Academically, the expression of NPY is evidenced to decline in mice with depression [ 35 ].…”

“…NPY is a hypothalamic orexigenic neuropeptide which is sufficient to prevent anxiety, social disorders and depressive symptoms [ 16 ]. Besides that, NPY and its receptors have been evidenced to impose anti-inflammatory and antidepressant effects on lipopolysaccharides-induced depression rat models [ 17 ]. Taken together, the combined interplay of HDAC1/miR-124-5p/NPY axis in depression is in ambiguity.…”

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…Additionally, the results of the enzyme-linked immunosorbent assay showed that NPY and PYY 3–36 reversed the LPS-induced upregulation of IL-1β levels; this effect was also prevented by BIIE0246. These data suggest that NPY inhibits the NLRP3 pathway through Y2R to prevent neuroinflammation ( 87 ). In conclusion, the activation of Y1R and Y2R holds a particular inhibitory capacity in the secretion of pro-inflammatory factors.…”

“…Nevertheless, Y5R antagonists also play an antidepressant role through the MAPK/ERK and PI3K signaling pathways ( 143 ). Besides, Y2R plays an antidepressant role by inhibiting the NLRP3 signaling pathway in LPS-induced depression model rats ( 87 ). Intriguingly, in turn, the depression-induced increase in NPY expression affects immune cell recruitment and cytokine secretion ( 18 ).…”

A multi-staged neuropeptide response to traumatic brain injury

“…Neuropeptide Y, as well as its selective NPY Y2 receptor agonist (NPY13-36), is known to act as an endogenous anticonvulsant by modulating glutamatergic hippocampal excitability [25], while displaying inhibitory action on cytotoxic cellular edema, by regulating KCl-evoked glutamate release [52]. Interestingly, NPY is co-localized with SP on GABAergic interneurons and A1 neurons in supra-optic nuclei (despite different ATP-stimulated actions on vasopressin and oxytocine release) [53], among other organs [54], with some authors suggesting that NPY might counterbalance SP's action, namely on nociceptive pathways and/or inflammation [55,56].…”