4-hydroxyisoleucine mediated IGF-1/GLP-1 signalling activation prevents propionic acid-induced autism-like behavioural phenotypes and neurochemical defects in experimental rats. (December 2022)

• Record Type: Journal Article
• Authors: Bhalla, Sonalika; Mehan, Sidharth
• Is Part Of: Neuropeptides. Volume 96(2022)
• Publication Date: 2022-12
• Subjects: Autism -- Propionic acid -- IGF-1 -- GLP-1 -- 4-Hydroxyisoleucine -- Neuroprotection; 4-HI 4-hydroxyisoleucine -- Ach Acetylcholine -- AchE Acetylcholinesterase -- AD Alzheimer's disease -- ALS Amyotrophic lateral sclerosis -- AP Anterior/posterior -- BCT Beam crossing task -- CNS Central nervous system -- CSF Cerebrospinal fluid -- DV Dorsal/ventral -- ELT Escape latency time -- FST Forced swim test -- GLP-1 Glucagon-like peptide-1 -- HD Huntington's disease -- IAEC Institutional Animal Ethics Committee -- ICH Intracerebral hemorrhage -- ICV-PPA Intracerebroventricular-propionic acid -- IGF-1 Insulin-like growth factor-1 -- IL-1β Interleukin 1 beta -- i.p. Intraperitoneally -- LDH Lactate dehydrogenase -- LFB Luxol fast blue -- LRG Liraglutide -- MBP Myelin basic protein -- MDA Malondialdehyde -- ML Medial/lateral -- MWM Morris water maze -- NEF-L Neurofilament Light -- NO Nitric oxide -- PD Parkinson's disease -- ROS Reactive oxygen species -- SOD Superoxide dismutase -- TNF- α Tumornecrotic factor-alpha -- TSTQ Time spent in target quadrant; Neuropeptides -- Periodicals; Neuropeptides; Neuropeptides -- Périodiques; Neuropeptides; Electronic journals; Periodicals; 572.65
• DOI: 10.1016/j.npep.2022.102296
• Languages: English
• ISSNs: 0143-4179

Abstract

Abstract: Autism is a neuropsychiatric disorder characterized by a neurotransmitter imbalance that impairs neurodevelopment processes. Autism development is marked by communication difficulties, poor socio-emotional health, and cognitive impairment. Insulin-like growth factor-1 (IGF-1) and glucagon-like growth factor-1 (GLP-1) are responsible for regular neuronal growth and homeostasis. Autism progression has been linked to dysregulation of IGF-1/GLP-1 signalling. 4-hydroxyisoleucine (HI), a pharmacologically active amino acid produced from Trigonella foenum graecum, works as an insulin mimic and has neuroprotective properties. The GLP-1 analogue liraglutide (LRG) was employed in our investigation to compare the efficacy of 4-HI in autism prevention. The current study explores the protective effects of 4-HI 50 and 100 mg/kg orally on IGF-1/GLP-1 signalling activation in a PPA-induced experimental model of autism. Propionic acid (PPA) injections to rats by intracerebroventricular (ICV) route for the first 11 days of the experiment resulted in autism-like neurobehavioral, neurochemical, gross morphological, and histopathological abnormalities. In addition, we investigated the dose-dependent neuroprotective effects of 4-HI on the levels of several neurotransmitters and neuroinflammatory cytokines in rat brain homogenate and blood plasma. Neuronal apoptotic and anti-oxidant cellular markers were also studied in blood plasma and brain homogenate samples. Furthermore, the luxol fast blue (LFB) staining results demonstrated significant demyelination in the brains of PPA-induced rats reversed by 4-HI treatment. Rats were assessed for spontaneous locomotor impairments, neuromuscular coordination, stress-like behaviour, learning, and memory to assess neurobehavioral abnormalities. The administration of 4-HI and LRG significantly reversed the behavioural, gross and histological abnormalities in the PPA-treated rat brains. After treatment with 4-HI and LRG, LFB-stained photomicrographs of PPA-treated rats' brains demonstrated the recovery of white matter loss. Our findings indicate that 4-HI protects neurons in rats with autism by enhancing the IGF-1 and GLP-1 protein levels. Highlights: Intracerebral propionic acid infusion causes experimental autism. 4-hydroxyisoleucine (4-HI) improved behavioural and histopathological abnormalities. 4-HI alone and combined with Liraglutide restored neurochemicals in CSF, blood plasma and brain samples. 4-HI exerts neuroprotection by increasing IGF-1 and GLP-1 levels.