Final Report Summary - BRAINIK (Identification and validation of cerebral KCa3.1/KCa2.3 potassium channels a drug tragets for the prevention and treatment of cerebral ischemia associated with diabetes and Alzheimers disease)
Ion channels KCa3.1 and related KCa2 regulate cellular functions by producing important electrical changes of the cell (hyperpolarization) and thereby regulate the actions of the crucial intracellular second messenger, calcium, and inflammatory activity in peripheral organs and the central nervous system. In the body and especially in the brain they are expressed in the vascular endothelium and in activated pro-inflammatory microglia (central immune system cells) and some neurons. Channel functions are altered in several disease states characterized by neurodegeneration and chronic inflammatory processes. From the medical perspective, such mechanisms can be relevant for the development and progression central pathologies caused ischemia (stroke) and microglia-mediated neuronal survival or loss. From the pharmacological perspective, we proposed KCa3.1 proteins as potential treatment targets and therefore we developed and patented innovative types KCa3.1 inhibitors (so called gating modulators; patent (PCT/ES2015/070662) and currently test their utilities to alleviate disease in preclinical experimental studies and in model cell systems of patients’ cells as translational approach. Moreover, for target validation and efficacy studies we generated a murine model of inducible KCa3.1-overexpression to reveal the pro-inflammatory nature of KCa3.1 and the channel’s role in neurodegeneration. Other “proof-of-concept” studies conducted so far revealed efficacy of our compounds in models rodent models of neurodegeneration, i.e. multiple sclerosis and amyotrophic lateral sclerosis. Moreover, we found improved learning and physical activity in healthy mice. To the contrary, in our murine model of overexpression of KCa3.1 resulted in strong inflammatory response in several organs and motoric alterations. In sum, these studies provide strong evidence for the disease-alleviating efficacy of KCa3.1-inhibitors for the treatment of neuroinflammation and –degeneration.