Syringic Acid Prevents and Reverses Ketamine-induced Schizophrenia-like Memory Impairment

Background and Purpose: Alterations in the cholinergic-inflammatory pathway are believed to play a role in the cognitive symptoms of schizophrenia, a common neuropsychiatric condition characterised by altered perceptions of reality and impairments in learning and memory. In this study, we examined the preventive and reversal effects of syringic acid (SA), a naturally occurring phenolic metabolite with neuroprotective and anti-inflammatory properties, on ketamine-induced schizophrenia-like memory impairment, cholinergic deficits, and neuroinflammation. Methods: In the preventive protocol, mice received SA (50 or 100 mg/kg, p.o.) or risperidone (0.5 mg/kg) for 14 days before ketamine (20 mg/kg, i.p., days 8-14), with 30 min between treatments. In the reversal protocol, mice received ketamine (20 mg/kg, i.p.) daily for 14 days, then SA (50 or 100 mg/kg, p.o.) or risperidone (0.5 mg/kg) from days 8-14. Thereafter, we conducted behavioural tests, including the Y-maze test (YMT) and novel-object recognition test (NORT). The following day, mice were euthanised, and relevant brain regions such as the prefrontal cortex (PFC), striatum, and hippocampus involved in the disease were isolated for biochemical analyses, including acetylcholinesterase activity and nitrite levels, as well as immune markers such as interleukin-1beta (IL-1?), IL-10, and myeloperoxidase (MPO). Results: SA prevented and reversed ketamine-induced memory impairments. SA attenuated nitrergic and cholinergic deficits, as shown by reduced brain nitrite and acetylcholinesterase levels in the PFC, striatum, and hippocampus. It also decreased MPO activity and IL-1?, while increasing IL-10 in the PFC, striatum, and hippocampus. Conclusion: Together, SA attenuates ketamine-induced schizophrenia-like memory impairment through its combined antioxidant and modulation of cholinergic-anti-inflammatory pathways in the brains of mice.