Recently, it has been reported that metformin may attenuate inflammation and directly act on the central nervous system. Using the HPLC method, in Wistar rats, we assessed the changes in metformin concentrations in various brain regions (pituitary gland, olfactory bulb, hypothalamus, cerebellum, hippocampus, striatum, frontal cortex), cerebrospinal fluid and plasma after single and chronic oral administration, in the model of systemic inflammation induced by lipopolysaccharide (ip). Regarding the influence of systemic inflammation on metformin distribution, the pituitary gland demonstrated the highest its level after single and chronic administration (28.8 ± 3.5 nmol/g and 24.9 ± 3.2 nmol/g, respectively). We concluded that orally-dosed metformin rapidly crosses the blood-brain barrier and differently accumulates in structures of the central nervous system.

Authors believe that metformin-based therapy, a cornerstone in diabetes therapy, not only improves the prognosis of diabetics by reducing blood glucose but also by reducing oxidative stress, inflammatory cytokine production and the shift toward alternative activation of macrophages.

Recent evidence suggests that metformin shows beneficial effects in experimental models of neuroinflammatory diseases. The aim of the present study was to determine the effect of metformin on phagocytosis and acidification of lysosomal/endosomal compartments in rat primary microglia in the presence of lipopolysaccharide (LPS) and/or beta-peptides (25-35), (1-40), and (1-42). Metformin increased the phagocytosis of fluorescent microspheres in the presence or absence of all the beta-peptides. However, the drug had no effect on the phagocytosis in LPS-stimulated microglia regardless of the presence of all the beta-peptides. Metformin acidified the lysosomal/endosomal compartments in the presence or absence of the beta-peptide 1-40 in both resting and activated microglia. To elucidate the mechanism of metformin action, we used 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside as an activator of adenosine monophosphate-activated protein kinase (AMPK) and compound C as a confirmed pharmacological inhibitor of AMPK. We have shown that metformin increased AMPK activity in microglial cells and that all observed effects are AMPK-dependent because the pretreatment of microglia with compound C reversed the effects of the drug. Since degradation of proteins in lysosomal/endosomal compartments depends largely on their phagocytosis and acidification, metformin may be beneficial in proteinopathies affecting the brain.

AMP-activated kinase (AMPK) acts as the intracellular ATP depletion sensor, which detects and limits increases in the AMP/ATP ratio. AMPK may be significantly activated under stress conditions that deplete cellular ATP levels such as ischemia/hypoxia or glucose deprivation. Recent studies strongly suggest that AMPK participates in autophagy regulation, but it is not known whether AMPK activated by ischemia regulates autophagy in astrocytes and the consequence of autophagy activation in ischemic astrocytes are unclear. We have investigated the contribution of AMPK to autophagy activation in rat primary astrocyte cultures subjected to ischemia-simulating conditions (combined oxygen glucose deprivation, OGD) and its potential effects on astrocyte damage induced by OGD (1-12 h). The evidence supports the conclusion that AMPK activation at early stages of OGD is involved in induction of protective autophagy in astrocytes. Inhibition of AMPK, either by siAMPKα1 or by compound C, significantly attenuated the expression of autophagy-related proteins and decrease of astrocyte viability following OGD. The findings provide additional data about the role of AMPK in ischemic astrocytes and downstream responses that may be involved in OGD-induced protective autophagy.

The results of recent studies suggest that metformin, in addition to its efficacy in treating type 2 diabetes, may also have therapeutic potential for the treatment of neuroinflammatory diseases in which reactive microglia play an essential role. However, the molecular mechanisms by which metformin exerts its anti-inflammatory effects remain largely unknown. Adenosine-monophosphate-activated protein kinase (AMPK) activation is the most well-known mechanism of metformin action; however, some of the biological responses to metformin are not limited to AMPK activation but are mediated by AMPK-independent mechanisms. In this paper, we attempted to evaluate the effects of metformin on unstimulated and LPS-activated rat primary microglial cell cultures. The presented evidence supports the conclusion that metformin-activated AMPK participates in regulating the release of TNF-α. Furthermore, the effects of metformin on the release of IL-1β, IL-6, IL-10, TGF-β, NO, and ROS as well as on the expression of arginase I, iNOS, NF-κB p65 and PGC-1α were not AMPK-dependent, because pretreatment of LPS-activated microglia with compound C, a pharmacological inhibitor of AMPK, did not reverse the effect of metformin. Based on the present findings, we propose that the shift of microglia toward alternative activation may underlie the beneficial effects of metformin observed in animal models of neurological disorders.