Platelet derived growth factor PDGF and ciliary neurotrophic
Platelet-derived growth factor (PDGF) and ciliary neurotrophic factor (CNTF) are expressed by glial Amyloid Beta-Peptide (1-40) and are important to neuron survival and the maintenance of oligodendrocytes. These neurotrophic factors contribute to the remyelination process by increasing the proliferation of oligodendrocyte precursor cells (Linker et al., 2002, Vana et al., 2007). Paintlia et al. (2013) provide evidence that AMPK signaling is crucial to the protection of oligodendrocytes, restoring the integrity of the central nervous system and functions in animals with EAE. Treatment with metformin enhanced the expression of the signatory genes of oligodendrocyte lineage cells, CNTF and PDGF. Moreover, treatment with metformin abolished the expression of inflammatory mediators (TNF-α and iNOS), attenuated oxidative stress and malondialdehyde levels as well as promoted antioxidative defenses in oligodendrocytes exposed to cytokines via AMPK activation.
Another demyelinating experimental model regards the use of cuprizone, which is a copper quelant that induces the degeneration of the myelin sheath and the death of oligodendrocytes without affecting the peripheral immune system (Matsushima and Morell, 2001). Analyzing the neuroprotective and anti-inflammatory action of sildenafil, Nunes et al. (2015) demonstrated protective action of the pAMPK-IKBα-NFκB pathway in a CPZ demyelination model. After treatment with sildenafil, both pAMPK and eNOS levels were significantly elevated, suggesting reciprocity between AMPK and eNOS. Treatment also reduced NFκB and increased IKβα. These data indicate that sildenafil activates AMPK, which, in turn, induces an increase in eNOS expression and NO production. The hypothesis is that NO starts the feedback loop, further activating AMPK and inhibiting NFκB.
In another study using the CPZ demyelinating model for eight weeks, the authors evaluated the protective action of the Areca catechu extract (ANE), which promoted improvements in cognition and social activity and protected myelin by promoting the differentiation of oligodendrocyte precursor cells. Contradictorily, the results also showed that the chronic administration of CPZ increased the phosphorylation level of AMPKα, which was suppressed by ANE treatment (Adilijiang et al., 2015). The conflicting AMPK results obtained could be related to the stage of the disease. However, the non-use of AMPK antagonists hinders the evaluation of the specific role of AMPK.
Neuropathies In diabetic neuropathy, demyelination and neuron damage lead to motor and sensory deficits. Some studies have indicated metformin as potential therapy for painful diabetic neuropathy. Ma et al. (2015) found that metformin attenuated diabetic hyperalgesia and allodynia. The authors report that metformin reduced levels of malondialdehyde and glycation end-products as well as enhanced superoxide dismutase activity. Moreover, metformin activated the phosphorylation of AMPK and its target genes in the sciatic nerve of diabetic rats, which may be associated with its anti-oxidative and neuroprotective effects. Through electrophysiological studies and behavioral analyses, Ma et al. (2016) also report that metformin exerts beneficial effects on nerve regeneration and functional recovery after sciatic nerve crush injury in diabetic rats. Interestingly, AMPK also exerts anti-inflammatory and neuroprotective effects on diabetes-induced neuropathy. Treatment with metformin reduced blood glucose levels, inflammatory markers (such as IL-6, C-reactive protein and TNF-α) and enhanced motor nerve conduction velocities (MNCV) of the sciatic nerve, which is an electrophysiological marker for peripheral nerve damage. Co-administration of Compound C with metformin counteracted these effects. The results indicate that the anti-inflammatory effects of metformin in diabetic neuropathy may be associated with the AMPK signaling pathway (Hasanvand et al., 2016).