Berberine improves inhibitory avoidance memory impairment of Toxoplasma gondii-infected rat model of ketamine-induced schizophrenia

Abstract

Background: Memory impairment caused by Toxoplasma gondii infection has been documented. Berberine (BRB) is well known for its enhancing effects on memory and has shown promising results. However, the impact of BRB on T. gondii infection and schizophrenia-induced consolidation and reconsolidation memory impairment is still unclear. Here; we examined the effect of BRB on the inhibitory avoidance (IA) memory consolidation and reconsolidation impairment induced by T. gondii infection, and ketamine (Ket) as a pharmacological model of schizophrenia. Also; the brain-derived neurotrophic factor (BDNF) levels in the medial prefrontal cortex (mPFC) and hippocampus were analyzed.

Methods: Rats were infected with T. gondii RH strain or received Ket (30 mg/kg/day) intraperitoneally (i.p) for at least five consecutive days (as the model of schizophrenia). Then followed by oral administration with BRB (25 mg/kg/day) for five days. Finally, the IA memory retention test was examined 48 post-conditioning, and BDNF was measured.

Results: Results indicated IA memory impairment in T. gondii-infected animals since lower step-through latency (STL) was observed than in control animals. We found significant (P = 0.01, P = 0.001) elevations in STL and a significant decrease (P = 0.001) in total time spent in the dark area following BRB administration in infected and Ket-treated rats, indicating improvement (increased STL) in consolidation and reconsolidation memory. Moreover, BDNF levels were reduced (P = 0.01) in the hippocampus and mPFC regions of both T. gondii- infected and Ket-induced groups, which remarkably enhanced after BRB treatment. Furthermore; we found that BRB administration notably increased the mPFC BDNF levels in mPFC (P < 0.01) and hippocampus (P = 0.001) in the Ket-treated and rats infected with T. gondii.

Conclusion: Taken together; BRB may be a valuable preclinical treatment for improving memory impairment through BDNF expression in PFC and hippocampus, therefore; BRB is suggested for memory disturbances induced by T. gondii infection.

Keywords: Berberine; Consolidation; Inhibitory avoidance memory; Reconsolidation; Schizophrenia rat model; Toxoplasma gondii.

Fig. 1

Time-line of the protocol used in all experiments, Cyc-A: Cyclosporin A; HCA: Hydrocortisone acetate; TOXO: toxoplsma; SAL: saline; Cont: control; Ket: Ketamine; BRB: Berberine; IA: inhibitory avoidance; BDNF: brain-derived neurotrophic factor

Fig. 2

T. gondii DNA was detected by the using 529-bp repeat gene in rat brain tissues of chronic toxoplasma after two-month infection. Negative: D.W, Positive: RH strain of T. gondii DNA, 1–10: brain tissue DNA samples

Fig. 3

Effects of exposure to Ket and T.gondii infection on inhibitory avoidance consolidation in infected and non-infected rats. (A) STL, (B) time spent in the dark compartment, (C) and the number of entries to the dark compartment, (n = 8 rats in each group). **P = 0.01, ***P = 0. 001 compared to the control group, ^# P < 0.05, ^## P = 0.01, compared to Toxo-infected rats, ^$$ P = 0.001 compared to the Ket-induced rats. Cont: control; Ket: Ketamine; BRB: Berberine; STL: Step through latency

Fig. 4

Effects of exposure to Ket and T. gondii infection on inhibitory avoidance reconsolidation in infected and non-infected rats. (A) STL, (B) time spent in the dark compartment, (C) and the number of entries to the dark compartment (Fig. 2A–C respectively) (n = 8 rats in each group). * P < 0.05, **P = 0.01, ***P = 0. 001 compared to the control group, ^## P = 0.01, ^### P = 0.001, compared to toxo infected rats, $$ P = 0.001 compared to the Ket-induced rats. Cont: control; Ket: Ketamine; BRB: Berberine; STL: Step through latency

Fig. 5

Effects of exposure to Ket and T. gondii infection on (A) BDNF expression in PFC and (B) in the hippocampus. * P < 0.05 and **P = 0.01 compared to the control group, ^# P < 0.05, ^## P = 0.01, compared to toxo infected rats, ^$ P < 0.05 and ^$$ P = 0.001 compared to the Ket-induced rats. Cont: control; Ket: Ketamine; BRB: Berberine; STL: Step through latency; Cont: control; Ket: Ketamine; BRB: Berberine; BDNF: Brain-derived neurotrophic factor; PFC: Prefrontal cortex; STL: Step through latency