Akademik Veri Yönetim Sistemi
Neuroscience Applied, cilt.2, ss.101019-101045, 2023 (Hakemli Dergi)
Backrounds: Schizophrenia is a devastating psychiatric disorder with complex symptoms and neurobiology, affecting approximately 1% of the world's population. Studies have shown that exposure to viral and bacterial infections during pregnancy increases the risk of neurodevelopmental disorders including schizophrenia and autism disorders [1-2]. Injection of polyinosinic-polycytidylic acid (Poly I:C) to in pregnant rodents can induce maternal immune activation leading to impairments in brain function associated with neurodevelopmental defects in the offspring [3]. While 15% success is achieved in the treatment of negative and cognitive symptoms, 35% success is achieved in positive symptoms with current pharmacotherapy [1]. Ivermectin acts as a positive allosteric modulator of several ligand-gated channels including neuronal alpha7-nicotinic receptor, gamma aminobutyric acid type-A receptor, glycine receptor, and purinergic P2X4 receptor [4]. The α7 nicotinic acetylcholine receptors (nAChR) agonism is one of the new treatment targets in schizophrenia. Herein, we aimed to investigate the effect of ivermectin on behavioral and neurobiological deficits of schizophrenia in rats.
Methods: Wistar albino rats were grouped as the following: Control, Poly I:C (8 mg/kg), Poly I:C+ivermectin (0.5 mg/kg), Poly I:C+ivermectin (1 mg/kg), Poly I:C+ivermectin (2 mg/kg). Poly I:C (8 mg/kg) was administered subcutaneously to pregnant rats at the 15th day of pregnancy to produce the schizophrenia model. After the Poly I:C Induced Maternal Immune Activation Model of Schizophrenia was established, ivermectin was injected to offspring rats for 21 days and social interaction, novel object recognition and prepulse inhibition tests were performed on the 16th, 17th-18th, and 19th-20th days of treatments, respectively. After the treatment regimen, the rats were decapitated and brain cytokines levels were analyzed by ELISA test.
Result: Poly I:C administration caused a significant decrease (p<0.0001) in the discrimination index compared with the Poly I:C group whereas ivermectin markedly increased (p<0.0001) the discrimination index with increasing dose. Besides, Poly I:C group has decreased sniffing (p<0.0001), following (p<0.0001), and climbing (p<0.0001) and increased the avoiding behaviors (p>0.0001) compared to the control group. Ivermectin increased (p<0.001) sniffing, following and climbing behaviors and decreased (p<0.001) avoiding behavior compared to Poly I:C group. Poly I:C reduced (p<001) prepulse inhibition (%) compared to control while ivermectin enhanced (p<0.001) prepulse inhibition in comparison with Poly I:C. Moreover, as a result of Poly I:C application, IL-1β levels increased in the hippocampus (p<0.01) and frontal cortex (p<0.05) while ivermectin treatment decreased (p<0.05) IL-1β expression in these brain regions.
Conclusion: Herein, we first suggested a potential therapeutic effect of ivermectin, a positive allosteric modulator of the neuronal alpha 7 nicotinic receptor, especially cognitive and negative symptoms of schizophrenia in Poly I:C model in rats. It would be beneficial to validate our study in different rodent models of schizophrenia and to investigate the possible mechanisms underlying these effects and to support it with in vivo efficacy and safety tests in further studies.