Feed-added Inulin mitigates ketamine-induced behaviours and hippocampal neurotoxicity via modulation of gut Lactobacilli count and brain oxidative stress

Lawal Ismail Adetayo¹, Onaolapo Olakunle James², Onaolapo Adejoke Yetunde³

1. Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, Al-hikmah University, Ilorin, Nigeria, ORCID: 0000-0002-0584
2. BehaviouralNeuroscience and Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria, orcid.org/0000-0003-2142-6046
3. Behavioural Neuroscience and Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria, orcid.org/0000-0001-7126-7050

ABSTRACT

Schizophrenia is a complex psychiatric disorder characterised by positive and negative symptoms, with current pharmacotherapies showing limited efficacy in managing negative symptoms. Hence, the problem of treatment resistance and high relapse rates. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is frequently used to induce schizophrenia-like symptoms in rodents. Recent research has highlighted the gut-brain axis as a novel target for mitigating schizophrenia disorder, with prebiotics such as inulin demonstrating potential in modulating neurobehavior through antioxidant properties and neurotransmitter regulation. Eighty (80) male mice were randomly assigned into eight groups (n=10). Group A received normal saline (control), Groups B - D were administered inulin in feed at 2g, 4g, and 8g/kg, Group E received ketamine alone (50 mg/kg, intraperitoneally), and Groups F, G and H received ketamine followed by inulin supplemented feed. Ketamine and saline were administered intraperitoneally for 5 days, while inulin was fed to them for 30 days. Faecal samples were collected weekly for Lactobacillus quantification. On day 36, behavioural tests (social interaction and Y-maze) were conducted. On day 37, animals were sacrificed for histological (haematoxylin and eosin and cresyl fast violet staining, biochemical analyses including lipid peroxidation, total antioxidant capacity and nitric oxide levels. Results revealed that ketamine-treated mice exhibited social withdrawal, oxidative stress and evidence of hippocampal neurotoxicity. The administration of Inulin however reversed Ketamine induced behavioural and hippocampal alterations. In conclusion this study has demonstrated the benefits of feed-added inulin in mitigating ketamine induced schizophrenia-like behaviours and hippocampal neurotoxicity in mice, however more studies are required to ascertain its beneficials effects in humans.

KEYWORDS: Schizophrenia, Ketamine Model, Inulin, Gut-Brain Axis, Oxidative Stress