Kim et al found that hydroxydopamine

Kim et al. (2013) found that 6-hydroxydopamine (6-OHDA) promoted the atrophy of dopaminergic neurons associated with the activation of poly (ADP-ribose) polymerase (PARP), the translocation of apoptosis inductor factor (AIF) and the depletion of ATP. An increase in p-AMPK and pS6K (upstream kinase of the mTOR pathway) accompanied ATP depletion from the third day to the 14th day. These neurotoxicity effects of 6-OHDA were abolished in PARP KO mice. Treatment with metformin did not cause harm to dopaminergic neurons in control animals, but reduced the survival of dopaminergic neurons, deceased TH-positive Verdinexor and increased both p-c-Jun and AIF translocation in the 6-OHDA-PD model. Moreover, adenovirus carrying dominant-negative mutant AMPKα2 cDNA blocked the inhibition of ACC, restored the expression of TH as well as induced c-Jun phosphorylation and AIF translocation, thereby preventing 6-OHDA-induced atrophic changes in dopaminergic neurons (Kim et al., 2013). It is well-know that glial activation and inflammation contribute to neuronal dysfunction and play an important role in the pathophysiology of Parkinson's (Tansey et al., 2007, Tansey and Goldberg, 2010). Thus, AMPK could represent a possible therapeutic target. However, the effects of AMPK on dopaminergic neurons are contradictory. It is not yet possible to conclude whether the elevation in pAMPK levels causes harm to dopaminergic neurons or can promote neuronal survival, since experimental models that mimetic Parkinson's pathophysiology act by deregulating the activity of mitochondrial complex I, which indeed increases AMP/ATP and ADP/ATP ratios and ultimately activates AMPK, making the results unclear.
Diabetic encephalopathy and Alzheimer's disease Diabetic encephalopathy, which is characterized by cognitive decline and dementia, commonly occurs in elderly patients with long-standing diabetes and is also considered a risk factor for Alzheimer's disease (Abdelhafiz et al., 2015). The pathological hallmarks associated with Alzheimer's disease are hyperphosphorylated tau protein, which causes intracellular neurofibrillary tangles, and extracellular deposits of β-amyloid (Aβ), generating senile plaques (Querfurth and LaFerla, 2010, Montine et al., 2012), which are related to late-onset sporadic Alzheimer's. There is also familial early-onset Alzheimer's, which is correlated to mutations in genes encoding for amyloid precursor protein (APP) and/or presenilin 1 and 2 (PS1 and 2) (Goate et al., 1991, Levy-Lahad et al., 1995, Schellenberg et al., 1992). Metabolic defects correlate diabetic encephalopathy and Alzheimer's, since insulin modulates the metabolism of amyloid peptides, which are derived from sequential proteolytic cleavages of full-length amyloid precursor protein by β-secretase (BACE1) and γ-secretase in neurons, thereby decreasing the intracellular accumulation of Aβ peptides (Chen et al., 2009). The disruption of insulin signaling is associated with the two neuropathological hallmarks of Alzheimer's: senile plaques and neurofibrillary tangles. Peripheral hyperinsulinemia and insulin resistance characterizes type 2 diabetes, whereas type 1 diabetes is associated with systemic insulin deficiency. Under conditions of hyperinsulinemia, insulin competes with Aβ for the action of the insulin degrading enzyme. Thus, excess insulin reduces the degradation of Aβ peptides. Moreover, GSK-3β, which is a protein kinase of tau (Ishiguro et al., 1992), is phosphorylated and inactivated by the insulin signaling pathway. Thus, impairment of the insulin/insulin receptor potentiates the hyperphosphorylation of tau and the formation of neurofibrillary tangles (reviewed in Correia et al., 2012). The hippocampus of db/db mice (type 2 diabetes model) exhibits an increase in tau protein kinase (JNK), phosphorylated tau (p-tau) at S396 and total tau (Sadeghi et al., 2017). When these animals were treated with metformin, no beneficial or detrimental effects were found on spatial learning or memory; however, metformin reduced p-tau, total tau and JNK levels and led to the recovery of synaptophysin expression, which is a synaptic protein (Li et al., 2012).