Curcumin Potentiates α7 Nicotinic Acetylcholine Receptors and Alleviates Autistic-Like Social Deficits and Brain Oxidative Stress Status in Mice

Abstract

Autistic spectrum disorder (ASD) refers to a group of neurodevelopmental disorders characterized by impaired social interaction and cognitive deficit, restricted repetitive behaviors, altered immune responses, and imbalanced oxidative stress status. In recent years, there has been a growing interest in studying the role of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in the CNS. Influence of agonists for α7-nAChRs on the cognitive behavior, learning, and memory formation has been demonstrated in neuro-pathological condition such as ASD and attention-deficit hyperactivity disorder (ADHD). Curcumin (CUR), the active compound of the spice turmeric, has been shown to act as a positive allosteric modulator of α7-nAChRs. Here we hypothesize that CUR, acting through α7-nAChRs, influences the neuropathology of ASD. In patch clamp studies, fast inward currents activated by choline, a selective agonist of α7-nAChRs, were significantly potentiated by CUR. Moreover, choline induced enhancement of spontaneous inhibitory postsynaptic currents was markedly increased in the presence of CUR. Furthermore, CUR (25, 50, and 100 mg/kg, i.p.) ameliorated dose-dependent social deficits without affecting locomotor activity or anxiety-like behaviors of tested male Black and Tan BRachyury (BTBR) mice. In addition, CUR (50 and 100 mg/kg, i.p.) mitigated oxidative stress status by restoring the decreased levels of superoxide dismutase (SOD) and catalase (CAT) in the hippocampus and the cerebellum of treated mice. Collectively, the observed results indicate that CUR potentiates α7-nAChRs in native central nervous system neurons, mitigates disturbed oxidative stress, and alleviates ASD-like features in BTBR mice used as an idiopathic rodent model of ASD, and may represent a promising novel pharmacological strategy for ASD treatment.

Keywords: BTBR mice; autism spectrum disorder; curcumin; nicotinic receptors; oxidative stress; positive allosteric modulator; social features.

Figure 1

Chemical structure of curcumin, the active compound of the spice turmeric.

Figure 2

The effect of curcumin on choline-induced ion currents recorded in CA1 area stratum radiatum interneurons of rat hippocampal slices. (A) Recordings of holding current in the presence of curcumin for 30 s (on the left), choline-induced currents before (control, second panel from left), during (5 min of curcumin) and after (2 min of recovery) the bath application of 1 µM curcumin in hippocampal interneurons. Choline application was represented with a short solid bar on top of the current traces. The dashed line indicates continuing bath application of curcumin. (B) Time-course of the effect of vehicle (0.1% DMSO; open circles) and curcumin (1 µM; filled circles) on the peaks of the Choline-induced currents. Each data point represents the normalized mean ± S.E.M. of five to seven experiments. The duration of drug application is indicated by the horizontal bar in the figure. (C) Summary of the effects of curcumin and methyllycaconitine on the peak amplitudes of choline induced currents. Bars represent the means ± S.E. of four to eight experiments (* p < 0.05 vs. control; ANOVA). MLA, methyllycaconitine.

Figure 3

The effect of curcumin on choline-induced enhancement of GABAA receptor-mediated spontaneous synaptic events in CA1 pyramidal neurons. Whole-cell recordings were performed using CsCl-based electrode solution at a holding potential of −70 mV. (A) On the left, the application of choline (2 mM) for 30 s increased the amplitudes and frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs; n = 6). On the right, in another cell, choline-induced enhancements of sIPSCs were increased significantly after 2 min preincubation in curcumin (1 µM). (B) Summary of the effects of curcumin (1 µM) on choline-induced responses. The averaged amplitudes (on the left) and the frequencies (on the right) of sIPSCs were presented before (control C, gray bars) and after (black bars) choline (Chol. 2 mM) application. For comparison, the effect of choline on the GABAA receptor-mediated sIPSCs is shown in the absence and the presence of curcumin. Bars represent the means ± S.E. of six to eight experiments (* p < 0.05 vs. control; ANOVA). C, control; Chol., choline.

Figure 4

Effects of curcumin and donepezil on deficits of sociability and social novelty preference in BTBR mice. After 10 min of habituation, male subjects were allowed to explore all chambers for two 10 min sessions. C57 and BTBR mice were injected with saline, and BTBR mice were administered with CUR (25, 50, or 100 mg/kg, i.p.) or DOZ (1 mg/kg, i.p.) chronically for 21 days. The results obtained were Sociability Index (SI) and Social Novelty Index (SNI) (B). Also, the effects of chronic (21 days) systemic co-injection of MLA (1 µg/kg, i.p.) on the CUR-(50 mg)-provided improvement of sociability (A) and social novelty preference (B) were assessed. Figures show mean ± SEM (n = 7). * p < 0.05 vs. SI or SNI of saline-treated C57 mice. ^## p < 0.01 vs. SI of saline-treated BTBR mice. ^### p < 0.001 vs. SI or SNI of saline-treated BTBR mice. ^$$ p < 0.05 vs. CUR-(50 mg)-treated BTBR mice.