A peptide blocking the ADORA1-neurabin interaction is anticonvulsant and inhibits epilepsy in an Alzheimer’s model
Shalini Saggu, Yunjia Chen, Liping Chen, Diana Pizarro, Sandipan Pati, Wen Jing Law, Lori McMahon, Kai Jiao, Qin Wang
Shalini Saggu, Yunjia Chen, Liping Chen, Diana Pizarro, Sandipan Pati, Wen Jing Law, Lori McMahon, Kai Jiao, Qin Wang
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Research Article Neuroscience Therapeutics

A peptide blocking the ADORA1-neurabin interaction is anticonvulsant and inhibits epilepsy in an Alzheimer’s model

Abstract

Epileptic seizures are common sequelae of stroke, acute brain injury, and chronic neurodegenerative diseases, including Alzheimer’s disease (AD), and cannot be effectively controlled in approximately 40% of patients, necessitating the development of novel therapeutic agents. Activation of the A1 receptor (A1R) by endogenous adenosine is an intrinsic mechanism to self-terminate seizures and protect neurons from excitotoxicity. However, targeting A1R for neurological disorders has been hindered by side effects associated with its broad expression outside the nervous system. Here we aim to target the neural-specific A1R/neurabin/regulator of G protein signaling 4 (A1R/neurabin/RGS4) complex that dictates A1R signaling strength and response outcome in the brain. We developed a peptide that blocks the A1R-neurabin interaction to enhance A1R activity. Intracerebroventricular or i.n. administration of this peptide shows marked protection against kainate-induced seizures and neuronal death. Furthermore, in an AD mouse model with spontaneous seizures, nasal delivery of this blocking peptide reduces epileptic spike frequency. Significantly, the anticonvulsant and neuroprotective effects of this peptide are achieved through enhanced A1R function in response to endogenous adenosine in the brain, thus, avoiding side effects associated with A1R activation in peripheral tissues and organs. Our study informs potentially new anti-seizure therapy applicable to epilepsy and other neurological illness with comorbid seizures.

Authors

Shalini Saggu, Yunjia Chen, Liping Chen, Diana Pizarro, Sandipan Pati, Wen Jing Law, Lori McMahon, Kai Jiao, Qin Wang

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Figure 2

A1R-induced inhibition of synaptic transmission is enhanced in mice without neurabin or RGS4 expression.

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A1R-induced inhibition of synaptic transmission is enhanced in mice with...
(A) Representative traces of fEPSP at CA3-CA1 synapses in hippocampal slices from WT mice treated with different concentrations of R-PIA. (B) Summary plot of mouse hippocampal slices exposed to R-PIA (min 20–50) showing the reduction of the fEPSP during bath application of 10 nM (n = 5), 30nM (n = 4), and 100nM (n = 4) R-PIA in WT brain slices. The amplitude of fEPSP slope was normalized to its baseline amplitude. (C) Statistical inhibitory effect of fEPSP slope by 10 nM, 30 nM, and 100 nM R-PIA on slices from WT mice. (D) Representative traces of fEPSP recorded during a 180 ms (at bar) in slices from WT, neurabin-deficient (Ppp1r9a–/–), and RGS4-deficient (Rgs4–/–) mice. (E) Summary plot of mouse hippocampal slices exposed to 10nM R-PIA (min 20–50) showing a larger magnitude depression in Ppp1r9a–/– and Rgs4–/– mice than in WT mice. The amplitude of fEPSP slope was normalized to its baseline amplitude. n = 4/group. (F) Summary of inhibition of 10 nM R-PIA on slices from WT, Ppp1r9a–/–, and Rgs4–/– mice, respectively. *P < 0.05 by 1-way ANOVA multiple comparisons. n = 4/group. Data were shown as mean ± SEM.