Current understanding of TRPM7 pharmacology and drug development for stroke

Abstract

The initial excitement and countless efforts to find a pharmacological agent that disrupts the excitotoxic pathway of ischemic neuronal death have only led to disappointing clinical trials. Currently, a thrombolytic agent called recombinant tissue plasminogen activator (rt-PA) is the only pharmacological treatment available for patients with acute ischemic stroke in most countries. Even though its efficacy has been confirmed repeatedly, rt-PA is considerably underused due to reasons including a short therapeutic window and repeated complications associated with its use. A search for alternative mechanisms that may operate dependently or independently with the well-established excitotoxic mechanism has led researchers to the discovery of newly described non-glutamate mechanisms. Among the latter, transient receptor potential melastatin 7 (TRPM7) is one of the important nonglutamate mechanisms in stroke, which has been evaluated in both in-vitro and in-vivo. In this review, we will discuss the current state of pharmacological treatments of ischemic stroke and provide evidence that TRPM7 is a promising therapeutic target of stroke.

Figure 1

(A) Schematic diagram of molecular pathways during ischemia including the traditional glutamate dependent mechanism and newly discovered non-glutamate dependent mechanisms. Glutamate dependent mechanism of cerebral ischemia is the most extensively studied mechanism and it is thought that energy failure due to ischemia leads to depolarization of presynaptic neurons, which leads to a massive release of glutamate. Increased glutamate in the extracellular space hyper-activates glutamate receptors, which consequently leads to excitotoxic Ca²⁺ overload. Recently, other non-glutamate dependent mechanisms that may contribute to the overall ionic imbalance have been discovered and these are: TRPM7, ASICs, VRACs, hemichannels, K_ATP, NCXs, and NSCCs. These pathways may even interact with each other suggesting complex molecular cascades upon ischemic insults. (B) Current working model of TRPM7 activation during cerebral Ischemia. Ischemic conditions are associated with decreases in extracellular pH (acidic) and concentrations of divalent ions (Ca²⁺ and Mg²⁺) and these changes may activate TRPM7 independent of other pathways. The initial influx of Ca²⁺via glutamate-dependent pathway stimulates productions of nitrogen oxide (NO) and superoxide (O₂⁻) and these combine to produce peroxynitrite (ONOO⁻). These reactive oxygen species and reactive nitrogen species (ROS and RNS) further promote sustained activation of TRPM7, which consequently causes a prolonged build up of intracellular Ca²⁺ leading to ischemic damages.