Recently Kamoshita et al evaluated a mouse model of retinal

Recently, Kamoshita et al. (2016) evaluated a mouse model of retinal neuronal disturbance with the intraperitoneal injection of LPS and found that treatment with AICAR suppressed the reduction of conical function and decreased mRNA levels of TNF-α as well as improved mRNA levels of the mitochondrial biogenesis regulator PGC-1α. Moreover, 24h after the injection of LPS, treatment with AICAR suppressed the expression of the glial fibrillary acidic protein (GFAP). However, other studies performed on neuronal cell lines support the hypothesis that AMPK activation is detrimental, as AICAR promoted apoptosis in undifferentiated human neuroblastoma cells (SH-SY5Y) through an increase in caspase-3 activity (Garcia-Gil et al., 2003). Similar results were found in mouse Neuro 2a neuroblastoma cells (Eun et al., 2004). Kainic ABT synthesis is a potent agonist of glutamate receptors that induces excitotoxicity and apoptosis in hippocampal neurons. Ullah et al. (2014) found that treatment with kainic acid significantly decreased cell viability, elevated the generation of radical oxygen species (ROS), increased intracellular Ca2+ levels and led to the loss of mitochondrial membrane potential. Kainic acid also induced the upregulation of Bax, decreased Bcl-2 levels, released cytochrome-c and activated caspase-3. All these events were accompanied by sustained phosphorylation and the activation of AMPK, possibly due a bioenergetic dysregulation. These conflicting results regarding the role of AMPK may reflect a dual function of this enzyme in regulating cell death and survival depending on the type of stress (Ramamurthy and Ronnett, 2006). Moreover, the role of AMPK in vivo is very likely different from that observed in vitro, especially in neurons. Neurons are postmitotic cells that have low energy reserves and are intolerant of cell stress, especially when examined without the supportive glial cells and vasculature that characterize the in vivo condition. The metabolic functions of neurons and astrocytes are distinct and there are complex interactions between these two types of cells during energy depletion. Therefore, analyses regarding the role of AMPK in neuroinflammation should take into account the cell-specific context.
Parkinson's disease Parkinson's disease is characterized by the degeneration of dopaminergic neurons of the substantia nigra pars compacta, the presence of Lewy bodies (α-synuclein) and motor alterations (Stocchi and Olanow, 2003). The etiology of Parkinson's disease is unknown, although some genes are associated to familiar Parkinson's disease (Tansey et al., 2007, Tansey and Goldberg, 2010). Recent studies suggest that intestinal inflammation may contribute to the development of neurodegenerative conditions. Individuals with Parkinson's exhibit inflammation and oxidative stress in the gut characterized by constipation, intestinal permeability, dysbiosis and increased levels of potentially pathogenic forms of enteric αSYN. Synucleinopathy exacerbates inflammation, inducing chronic systemic immune responses that, among other consequences, can increase the permeability of the blood-brain barrier. Moreover, aggregated αSYN can be transmitted from the gut to the brain via the vagus nerve, where it activates microglia, accelerating the timeline by which neuroinflammation induces degeneration of the central nervous system (see review in Houser and Tansey, 2017). The use of inhibitors of complex 1 mitochondrial, such as 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) and rotenone, as well as genetic mouse models of mitochondrial dysfunction to develop Parkinson's symptoms, lend support to the hypothesis that mitochondrial activity is relevant to the development of Parkinson's disease (Hang et al., 2015). Several studies indicate that energetic homeostasis is crucial to dopaminergic neurons; however, the neuronal effects of AMPK activation are controversial, as activation may be either protective or detrimental (Choi et al., 2010, McCullough et al., 2005).