Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia

Abstract

Cardiac arrest victims may experience transient brain hypoperfusion leading to delayed death of hippocampal CA1 neurons and cognitive impairment. We prevented this in adult rats by inhibiting the expression of transient receptor potential melastatin 7 (TRPM7), a transient receptor potential channel that is essential for embryonic development, is necessary for cell survival and trace ion homeostasis in vitro, and whose global deletion in mice is lethal. TRPM7 was suppressed in CA1 neurons by intrahippocampal injections of viral vectors bearing shRNA specific for TRPM7. This had no ill effect on animal survival, neuronal and dendritic morphology, neuronal excitability, or synaptic plasticity, as exemplified by robust long-term potentiation (LTP). However, TRPM7 suppression made neurons resistant to ischemic death after brain ischemia and preserved neuronal morphology and function. Also, it prevented ischemia-induced deficits in LTP and preserved performance in fear-associated and spatial-navigational memory tasks. Thus, regional suppression of TRPM7 is feasible, well tolerated and inhibits delayed neuronal death in vivo.

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…The activation of transient receptor potential melastatin (TRPM) channels, primarily the Ca 2+ -permeable TRPM2 (Lipski et al, 2006;Jia et al, 2011) and TRPM7 channels (Aarts et al, 2003;Sun et al, 2009), has been associated to oxidative stress, in addition to anoxic and ischemic cell death. Another key event during stroke is acidosis, caused by the decrease in the supply of oxygen to the brain, which leads to calcium influx, and failure of oxidative phosphorylation, with an increase in lactate production and the switch to glycolytic metabolism, with the final decrease in tissue pH (Xiong et al, 2004;Gu et al, 2010).…”

Activation of NR2A Receptors Induces Ischemic Tolerance through CREB Signaling

“…NR2A receptors in ischemic tolerance Y Terasaki et al receptor potential (TRP) channel and acid sensing ion channel can contribute to calcium accumulation that induces neuronal death (Sun et al, 2009;Xiong et al, 2004). Also, earlier study reported that TRPC6, one of the TRP channel subfamilies, was associated with CaMKIV-CREB-dependent gene transcription including BDNF .…”

TRPM7 in cerebral ischemia and potential target for drug development in stroke

“…To ease personal and societal burden of stroke, continuous efforts have been directed towards searching for new therapeutic targets in stroke. This review provides a current view on one of the non-glutamate mechanisms of stroke that mediates through TRPM7 channels from a recent in vivo study [4] . A major event during cerebral ischemia is a concomitant massive release of the excitatory neurotransmitter glutamate, which results in intracellular calcium overload and eventual cell death [5] .…”

“…Because of the limitation of the glutamate mechanism and the unfavourable outcomes of AET trials, stroke researchers have been seeking for alternative, non-glutamate related therapeutic targets that cause ionic imbalance and cell death. Some of these channels include: acid-sensing ion channels [16,17] , transient receptor potential (TRP) channels [4,7,[18][19][20][21] , and hemichannels [22][23][24] , volume-regulated anion channels [25] , sodium-calcium exchangers [26,27] and non-selective cation channels [28] . Based on the recommendations from the Stroke Therapy Academic Industry Roundtable (STAIR) committee, it is important to validate the preclinical development in proof of concept starting with in vivo rodent models as experimental animal stroke models [29] .…”