As a widely prescribed anti-diabetic drug, metformin (MTF) has been receiving novel attention for its analgesic potential. In the study of the complex etiology of neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher pain sensitivity and greater NeP incidence in women. This “gender gap” in our knowledge of sex differences in pain processing strongly limits the sex-oriented treatment of patients suffering from NeP. Besides, the current investigation of the analgesic potential of metformin has not addressed the “gender gap” problem. Hence, this study focuses on metformin and sex-dependent analgesia in a murine model of NeP induced by chronic constriction injury of the sciatic nerve. These authors investigated sexual dimorphism in signaling pathways involved by 7 days of MTF administration, such as changes in AMP-activated protein kinase and the positive regulation of autophagy machinery, discovering that MTF affected in a sexually dimorphic manner the immunological and inflammatory response to nerve lesion. These effects were complemented by morphological and adaptive changes occurring after peripheral nerve injury.
In their discussion, the authors note: The clinical interest in MTF-based therapy has been recently expanded to include several neurological disorders, mainly because of the parallel between some neuropathological mechanisms recognized in both type 1 and type 2 diabetes and neurodegenerative diseases such as Alzheimer’s disease. Indeed, energy dysfunction, failure in AMPK activation and disinhibition of mTORC1 signaling are mechanisms accountable for the deficit in protein translation underlying neurodegeneration as well as for the relationship between stimulation of autophagy machinery, MTF treatment, and relief from NeP. The sex-dependent assessment of MTF-induced AMPK phosphorylation revealed a lack of AMPK activation in female mice, while at Day 3, after CCI, the authors found the highest degree of AMPK activation in male animals, which was still higher at Day 7. Hence, such potential insensitivity to MTF-induced AMP phosphorylation in female mice may help to understand the absence of long-lasting functional recovery after peripheral nerve injury in female animals. Essentially, while in male mice, MTF treatment induces an early AMPK activation (as also reported with other autophagy inducers), in females showing a hyperactivated AMPK signaling, the MTF seems to induce a paradoxical effect, decreasing both AMPK and SIRT1 phosphorylation.
Altogether these data can contribute to explaining a number of potential mechanisms responsible for the complete recovery from NeP found in male mice, as opposed to the failure of long-lasting recovery in female animals.
Source: De Angelis F, Vacca V, Tofanicchio J, et al. Sex differences in neuropathy: the paradigmatic case of metformin. Int J Mol Sci. 2022;23(23):14503. doi: 10.3390/ijms232314503.
