Effects of caloric restriction on neuropathic pain, peripheral nerve degeneration and inflammation in normometabolic and autophagy defective prediabetic Ambra1 mice

Abstract

There is a growing interest on the role of autophagy in diabetes pathophysiology, where development of neuropathy is one of the most frequent comorbidities. We have previously demonstrated that neuropathic pain after nerve damage is exacerbated in autophagy-defective heterozygous Ambra1 mice. Here, we show the existence of a prediabetic state in Ambra1 mice, characterized by hyperglycemia, intolerance to glucose and insulin resistance. Thus, we further investigate the hypothesis that prediabetes may account for the exacerbation of allodynia and chronic pain and that counteracting the autophagy deficit may relieve the neuropathic condition. We took advantage from caloric restriction (CR) able to exert a double action: a powerful increase of autophagy and a control on the metabolic status. We found that CR ameliorates neuropathy throughout anti-inflammatory and metabolic mechanisms both in Ambra1 and in WT animals subjected to nerve injury. Moreover, we discovered that nerve lesion represents, per se, a metabolic stressor and CR reinstates glucose homeostasis, insulin resistance, incomplete fatty acid oxidation and energy metabolism. As autophagy inducer, CR promotes and anticipates Schwann cell autophagy via AMP-activated protein kinase (AMPK) that facilitates remyelination in peripheral nerve. In summary, we provide new evidence for the role of autophagy in glucose metabolism and identify in energy depletion by dietary restriction a therapeutic approach in the fight against neuropathic pain.

Impact of caloric restriction on peripheral nerve injury‐induced neuropathic pain during ageing in mice

“…Moreover CR had a proregenerative effect stimulating and accelerating the SCs proliferative processes since CDC2 and GAP43 were overexpressed in comparison to naïve and CCI ST mice. Besides we demonstrated (Coccurello et al, ) that adult peripheral nerve injured mice had high level of Schwann cells autophagy and that CR improved the myelin clearance facilitating remyelination; we did not find, instead, significant effects on myelin proteins expression in 12‐month‐old mice exposed to CR, even if the myelin resulted less aggregated and degenerated in respect of ST CCI mice. This apparent discrepancy can be explained by the evidence that ageing induces a patho‐physiological decline of autophagy activity (Rajendran et al, ) and a macrophages inefficiency (Khalil et al, ) leading to aggregates’ accumulation and to peripheral nerve deterioration.…”

“…Here, we induced a peripheral nerve damage in 12‐month‐old mice, an age that in mice introduces the senescence and, as expected, we observed mechanical hypersensitivity development, a high level of circulating pro‐inflammatory cytokines and chemokines, scarce presence of regenerative processes, differently from adult mice (Coccurello at al., ), and a strong degree of myelin degeneration.…”

“…Some studies have demonstrated its neuroprotective effects against ageing‐induced degeneration in peripheral nerves (Amer et al, ; Lee & Notterpeck, ; Rangaraju et al, ). Recently, we showed (Coccurello et al, ) in adult mice the therapeutic potential of a period of CR in counteracting NeP induced by nerve injury. In particular, CR was able to activate autophagy in Schwann cells accelerating processes of remyelination and regeneration, reducing proinflammatory cytokines both in sciatic nerves and in blood.…”

A Case of Suspected Hyperphenylalaninemia at Newborn Screening by Tandem Mass Spectrometry during Total Parenteral Nutrition

“…The internal standards, as well as the extraction solution, were obtained from the NeoBase 2Non-Derivatized MSMS Kit (Perkin Elmer Life and Analytical Sciences, Turku, Finland). Mass spectra were acquired in positive electrospray ionization, using multiple reaction monitoring (MRM) as acquisition mode, using an Ultra-Performance Liquid Chromatography/Tandem Quadrupole Mass Spectrometry (UPLC/MS/MS) system (Acquity UPLC I-Class coupled to a Xevo TQD, Waters Corp., Manchester, UK) [7][8][9]. Data were processed by MassLynx V4.2 and NeoLynx Software (Water Corp.).…”

“…In order to evaluate the metabolic alterations, further analyses for diagnostic confirmation were performed. UK) [7][8][9]. Data were processed by MassLynx V4.2 and NeoLynx Software (Water Corp.).…”