KATP Channel Opener Diazoxide Prevents Neurodegeneration: A New Mechanism of Action via Antioxidative Pathway Activation

Abstract

Pharmacological modulation of ATP-sensitive potassium channels has become a promising new therapeutic approach for the treatment of neurodegenerative diseases due to their role in mitochondrial and cellular protection. For instance, diazoxide, a well-known ATP-sensitive potassium channel activator with high affinity for mitochondrial component of the channel has been proved to be effective in animal models for different diseases such as Alzheimer’s disease, stroke or multiple sclerosis. Here, we analyzed the ability of diazoxide for protecting neurons front different neurotoxic insults in vitro and ex vivo. Results showed that diazoxide effectively protects NSC-34 motoneurons from glutamatergic, oxidative and inflammatory damage. Moreover, diazoxide decreased neuronal death in organotypic hippocampal slice cultures after exicitotoxicity and preserved myelin sheath in organotypic cerebellar cultures exposed to pro-inflammatory demyelinating damage. In addition, we demonstrated that one of the mechanisms of actions implied in the neuroprotective role of diazoxide is mediated by the activation of Nrf2 expression and nuclear translocation. Nrf2 expression was increased in NSC-34 neurons in vitro as well as in the spinal cord of experimental autoimmune encephalomyelitis animals orally administered with diazoxide. Thus, diazoxide is a neuroprotective agent against oxidative stress-induced damage and cellular dysfunction that can be beneficial for diseases such as multiple sclerosis.

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

“…; Virgili et al . ). In accordance with classic excitotoxic cell death pathways, elevated activity clearly is detrimental for SN DA survival, as it triggers energy demand, metabolic stress, and pathophysiological Ca 2+ overload, and its detrimental consequences (Blandini ; Surmeier et al .…”

“…In accordance with the classical 'use it or lose it' principle of neuronal plasticity and neuronal loss (Swaab et al 2002;Coyle 2003;Coulson et al 2008;Valenzuela et al 2012), reduced activity of SN DA neurons seems to facilitate their degeneration in vivo and in vitro (Salthun-Lassalle et al 2004;Liss et al 2005;Janezic et al 2013). On the other hand, reduced activity has also been shown to be beneficial for SN DA survival, particularly in acute pathophysiological demand situations (Liss et al 2005;Yamada and Inagaki 2005;Aumann et al 2008;Virgili et al 2013). In accordance with classic excitotoxic cell death pathways, elevated activity clearly is detrimental for SN DA survival, as it triggers energy demand, metabolic stress, and pathophysiological Ca 2+ overload, and its detrimental consequences (Blandini 2010;Surmeier et al 2011;Ambrosi et al 2014;Prentice et al 2015;Van Laar et al 2015).…”

Vitamin D cell signalling in health and disease

“…4). Opening of the mitochondrial K ATP channels by diazoxide reduces ROS formation [80,81]. The resulting hyperpolarization of the mitochondrial membrane potential will reduce both mitochondrial Ca 2þ uptake and the resulting increase in ROS production and this may explain the beneficial effects of diazoxide in neurodegenerative diseases such as AD [81] and multiple sclerosis (MS) [80].…”

Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic patients

“…It acts directly on the beta cells of the pancreas. It opens the K ATP channel and inhibits beta cells to secrete insulin . Diazoxide responsiveness of patients with PMM2‐CDG suggests that impaired function of K ATP channels could be a cause of hyperinsulinism in this disease.…”