Collapsin response mediator protein 2 (CRMP2), traditionally regarded as an axon/dendrite growth and guidance protein, plays an important role in the regulation of both post-and pre-synaptic Ca2+ channels, such as N-methyl-d-aspartate receptors (NMDARs). The Ca2+ channel-binding domain 3 (CBD3) peptide derived from CRMP2 has recently emerged as a Ca2+ channel blocker, suppressing neuropathic pain in a spared nerve injury (SNI) model when linked to the transduction domain of HIV TAT protein and reduced neuronal death in a middle cerebral artery occlusion model and a traumatic brain injury (TBI) model. The present study aimed to examine the neuroprotective effects and biochemical mechanisms of ST2-104 (a non-arginine-conjugated CBD3 peptide) in an A beta(25-35)-induced Alzheimer's disease (AD) rat model. This study demonstrated that CRMP2 and NMDARs subunit NMDAR2B form a direct biochemical complex, which regulates NMDAR activity in a rat model. ST2-104 peptide given via tail vein injections significantly reduced spatial learning and memory impairment. ST2-104 relieved neuronal injuries by suppressing expression of NMDAR2B and p-CRMP2 and increasing expression of CRMP2 in the hippocampus. Remarkably, ST2-104 attenuated levels of intracellular Ca2+ by disrupting the interaction between p-CRMP2 and NMDAR2B. Taken together, these findings support ST2-104 as a novel neuroprotective agent, potentially representing a novel direction for a therapeutic targeting channel in AD.
[1]Jilin Univ, Coll Basic Med Sci, Dept Pharmacol, Changchun 130021, Jilin, Peoples R China.
[2]Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA.
[3]Jilin Univ, Hosp 1, Dept Neurol, Changchun 130021, Jilin, Peoples R China.
[4]Jilin Univ, Hosp 1, Neurosci Ctr, Changchun 130021, Jilin, Peoples R China.
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