Rhynchophylline suppresses soluble Aβ1-42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B-containing NMDA receptors

Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. The overproduction of soluble amyloid β protein (Aβ) oligomers in the hippocampus is closely involved in impairments in cognitive function at the early stage of Alzheimer's disease (AD). Growing evidences show that RIN possesses neuroprotective effects against Aβ-induced neurotoxicity. However, whether RIN can prevent soluble Aβ_1-42-induced impairments in spatial cognitive function and synaptic plasticity is still unclear. Using the combined methods of behavioral tests, immunofluorescence and electrophysiological recordings, we characterized the key neuroprotective properties of RIN and its possible cellular and molecular mechanisms against soluble Aβ_1-42-related impairments in rats. Our findings are as follows: (1) RIN efficiently rescued the soluble Aβ_1-42-induced spatial learning and memory deficits in the Morris water maze test and prevented soluble Aβ_1-42-induced suppression in long term potentiation (LTP) in the entorhinal cortex (EC)-dentate gyrus (DG) circuit. (2) Excessive activation of extrasynaptic GluN2B-NMDAR and subsequent Ca²⁺ overload contributed to the soluble Aβ_1-42-induced impairments in spatial cognitive function and synaptic plasticity. (3) RIN prevented Aβ_1-42-induced excessive activation of extrasynaptic NMDARs by reducing extrasynaptic NMDARs -mediated excitatory postsynaptic currents and down regulating GluN2B-NMDAR expression in the DG region, which inhibited Aβ_1-42-induced Ca²⁺ overload mediated by extrasynanptic NMDARs. The results suggest that RIN could be an effective therapeutic candidate for cognitive impairment in AD.

Extrasynaptic NMDA receptor; Long term potentiation; Rhynchophylline; Soluble Aβ(1-42); Spatial cognition function.