Perisciatic Nerve Dexmedetomidine Alleviates Spinal Oxidative Stress and Improves Peripheral Mitochondrial Dynamic Equilibrium in a Neuropathic Pain Mouse Model in an AMPK-Dependent Manner

Abstract

Neuropathic pain (NPP) is a debilitating clinical condition that presently has few effective treatments. NPP is caused by uncontrolled central oxidative stress and inflammation. Preliminary studies indicate that dexmedetomidine (DEX), an agonist of the alpha-2 adrenergic receptor, is beneficial for treating NPP. In this paper, the effects of administering DEX around injured nerves in a chronic constriction injury- (CCI-) induced neuropathic pain mouse model are investigated. According to the results, the perineural DEX significantly reversed the decline in the mechanical threshold and thermal latency in CCI mice ( p < 0.001 ). In the peripherally affected ischiadic nerve, the perineuronal DEX upregulated the expressions of pAMPK, OPA1, and SNPH but not Drp1 or KIF5B. The aforementioned effects of administering DEX can be partially reversed by compound C, a selective and reversible inhibitor of AMP-activated protein kinase (AMPK). Furthermore, it was found that perineural DEX significantly inhibited the CCI-induced upregulation of the immediate early gene c-Fos, overexpression of the inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), attenuation of the NADH dehydrogenase complexes I, II, III, and IV, and the repression of ATP, SOD, and GSH in the dorsal horn of the spinal cord (DHSC) ( p < 0.01 ). These findings indicate that perineuronal DEX protected the injured ischiadic nerves and attenuated neuropathic pain via AMPK activation to improve energy supply in the peripheral injured nerves, alleviate the inflammatory factor release, and inhibit oxidative stress in the DHSC.

Cellular energy supply for promoting vascular remodeling of small-diameter vascular grafts: a preliminary study of a new strategy for vascular graft development

“…Mu et al found that dexmedetomidine, via the activation of AMPK, inhibited chronic constriction injury- (CCI-) induced decrease of the mitochondria respiratory chain complexes I, II, III, and IV, and the repression of ATP in the dorsal horn of the spinal cord. 45 AMPK is a key regulator of energy production in most cells. Koyani et al also claimed that the enhanced energy supply and anti-inflammatory action improved cardiovascular function via AMPK activation induced by empagliflozin in vivo and in vitro .…”

Dexmedetomidine promotes the functional recovery of mice after acute ischemic stroke via activation of the a2-adrenoceptor

“…DEX can reduce cognitive dysfunction following MCI in rats by inhibiting the release of inflammatory cytokines [41]. DEX can attenuate neuropathic pain by reducing the release of inflammatory factors and inhibiting oxidative stress [22].…”

Genetic polymorphisms of PRKAA1 (AMPKα1) and postherpetic pain susceptibility: Multicenter, randomized control, and haplotype analysis study

“…A characteristic feature of central sensitization is the activation of glial cells, such as microglia and astrocytes, in the spinal cord and brain, leading to the release of proinflammatory cytokines and chemokines ( Meacham et al, 2017 ). In a pilot animal study, we found the dysfunction of mitochondria play pivotal role in the activation of glial cells and hyperresponsiveness of neurons in spinal dorsal cord ( Mu et al, 2022 ). Dysfunction of mitochondria induced the inefficacy of energy supply and release of proinflammatory cytokines from glial cells, further induced abnormal membrane potential and synaptic plasticity in the vicinity of neurons.…”

“…The expression of phosphorylated AMPK (pho-AMPK) was significantly increased in the spinal dorsal horn and dorsal root ganglia of NeP rats in a chronic constriction injury of sciatic nerve (CCI) model ( Cui et al, 2011 ). Activation of AMPK can improve the energy supply of CCI-damaged nerves, relieve the release of inflammatory factors, and inhibit oxidative stress in the dorsal horn of the spinal cord, thus reducing neuropathic pain ( Mu et al, 2022 ). Three subunits (α, β, and γ) of AMPK were found and the α subunit is a functional unit ( Krishan et al, 2014 ).…”