Repurposing metformin to treat age-related neurodegenerative disorders and ischemic stroke

Abstract

Aging is a risk factor for major central nervous system (CNS) disorders. More specifically, aging can be inked to neurodegenerative diseases (NDs) because of its deteriorating impact on neurovascular unit (NVU). Metformin, a first line FDA-approved anti-diabetic drug, has gained increasing interest among researchers for its role in improving aging-related neurodegenerative disorders. Additionally, numerous studies have illustrated metformin's role in ischemic stroke, a cerebrovascular disorder in which the NVU becomes dysfunctional which can lead to permanent life-threatening disabilities. Considering metformin's beneficial preclinical actions on various disorders, and the drug's role in alleviating severity of these conditions through involvement in commonly characterized cellular pathways, we discuss the potential of metformin as a suitable drug candidate for repurposing in CNS disorders.

Keywords: Anti- aging; Diabetes; Electronic cigarette vaping; Ischemic stroke; Metformin; Neurodegenerative diseases; Tobacco smoking.

Figure 1:. Functional interactions among neurovascular unit components.

Interactions between the neuronal, glial and vascular compartments within the NVU are crucial for maintaining normal function of the brain. Also, different cells within each compartment are functioning and interacting cooperatively to regulate brain homeostasis.

Figure 2:

Effects of ageing on the NVU components and their interactions. Ageing can influence all the cells within the NVU and results in neurovascular uncoupling and neurodegeneration. In endothelial cells, ageing induces the secretion of pro-inflammatory factors such as TNF-a, IL-1B and VCAM-1, tight junctional protein disruption as a result of chronic neuroinflammation, and BBB impairment. It also increases astrocytic reactivity and impairs the role of astrocytic endfoot in connecting neurons and endothelial cells. BBB disruption and loss of communication with other cells result in neuronal dysfunction and neurodegeneration. Therefore, the regenerative capacities of neurons including synaptic plasticity, neurogenesis and synaptogenesis decrease significantly.

Figure 3:

Neuroprotective effects of metformin in ischemic stroke through AMPK signaling pathway. During an ischemic event, a series of neuroprotective mechanisms are stimulated by activated AMPK in order to maintain the energy homeostasis of the brain. Activated AMPK promotes autophagy, reduces neuroinflammation and oxidative stress by decreasing the levels of inflammatory factors (NF-KB, TNF-B, IL-1B, IL-6) and ROS production respectively. Also, it restrains apoptosis, glutamate excitotoxicity through inhibiting glutamate release and mitochondrial dysfunction therefore, promoting energy metabolism and glucose uptake.