Promising therapeutic efficacy of kolaviron against prenatal valproate-induced autism spectrum disorder

Articles in Press

Document Type : Original Article

Authors

1 Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

2 Cellular and Molecular Research Center, Iran university of Medical Sciences, Tehran, Iran

3 Neurophysiology Research Center, Shahed University, Tehran, Iran

10.22038/ijbms.2026.94595.20399

Abstract

Objective(s): Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition marked by impairments in social communication, language, and behavior. Prenatal exposure to valproic acid (VPA) contributes to its pathogenesis. kolaviron (KV), a polyphenolic extract from Garcinia kola, has potent antioxidant and anti-inflammatory properties, offering neuroprotective potential in ASD models. Our study aimed to evaluate whether KV could improve the VPA-induced autism model through targeting serotonergic system, mitochondrial dysregulation, oxidative stress, and inflammation.
Materials and Methods: Pregnant Wistar rats received a single intraperitoneal dose of VPA (600 mg/kg) on gestational day 12.5 to induce autism-like features in offspring. Male pups were weaned on postnatal day (PND) 21 and randomly assigned to receive KV (50 or 100 mg/kg, oral), or saline until PND 49. Behavioral tests were finally conducted and brain tissue was collected for analysis of hippocampal oxidative stress, mitochondrial dysfunction, serotonin transporter (5-HTT), serotonin receptor 7 (5-HTR7), tumor necrosis factor α (TNF), and interleukin 6 (IL-6) levels. Immunohistochemical staining for glial fibrillary acidic protein (GFAP) was also performed to assess astrocytic reaction.
Results: KV-treated VPA-exposed rats showed significant improvements in social interaction and with lower repetitive behavior. Biochemically, KV decreased malondialdehyde (MDA), IL-6 and TNFα levels, improved catalase activity and mitochondrial membrane potential (MMP), and modulated serotonergic markers (5-HTT and 5-HTR7). Histologically, KV also attenuated hippocampal GFAP immunoreactivity (IRA). 
Conclusion: KV showed its promising potential as a complementary therapeutic agent in ASD murine model. Further studies are still warranted to clarify its further mechanisms and clinical relevance.

Keywords

Main Subjects

References

1. Mehra S, Ul Ahsan A, Seth E, Chopra M. Critical evaluation of valproic acid-induced rodent models of autism: Current and future perspectives. J Mol Neurosci 2022; 72:1259–1273.
2. Gouda B, Sinha SN, Sangaraju R, Huynh T, Patangay S, Venkata Mullapudi S, et al. Extraction, phytochemical profile, and neuroprotective activity of Phyllanthus emblica fruit extract against sodium valproate-induced postnatal autism in BALB/c mice. Heliyon 2024; 10:e34992.
3. Kuźniar-Pałka A. The role of oxidative stress in autism spectrum disorder pathophysiology, diagnosis and treatment. Biomedicines 2025; 13:388.
4. Petruzzelli MG, Matera E, Margari L, Marzulli L, Gabellone A, Cotugno C, et al. An update on the comorbidity of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) and its clinical management. Expert Rev Neurother 2026; 26:75–89.
5. Afshari M, Gharibzadeh S, Pouretemad H, Roghani M. Promising therapeutic effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in addressing autism spectrum disorder induced by valproic acid. Front Neurosci 2024; 18:1385488.
6. Ukezono M, Kasahara Y, Yoshida C, Murakami Y, Okada T, Takano Y. Impairments of social interaction in a valproic acid model in mice. Front Behav Neurosci 2024; 18:1430267.
7. Al-Dossari AM, Al-Harbi LN, Al-Otaibi NM, Almubarak A, Almnaizel AT, Alshammari GM, et al. The potency of goat milk in reducing the induced neurotoxic effects of valproic acid in rat pups as a rodent model of autism spectrum disorder. Metabolites 2023; 13:497.
8. Kuo HY, Liu FC. Pathophysiological studies of monoaminergic neurotransmission systems in valproic acid-induced model of autism spectrum disorder. Biomedicines 2022; 10:560.
9. Farrag EAE, Askar MH, Abdallah Z, Mahmoud SM, Abdulhai EA, Abdelrazik E, et al. Comparative effect of atorvastatin and risperidone on modulation of TLR4/NF-kappaB/NOX-2 in a rat model of valproic acid-induced autism. Behav Brain Funct 2024; 20:26.
10. Nicolini C, Fahnestock M. The valproic acid-induced rodent model of autism. Exp Neurol 2018; 299:217–227.
11. Ayepola OR, Cerf ME, Brooks NL, Oguntibeju OO. kolaviron, a biflavonoid complex of Garcinia kola seeds modulates apoptosis by suppressing oxidative stress and inflammation in diabetes-induced nephrotoxic rats. Phytomedicine 2014; 21:1785–1793.
12. Farombi EO, Awogbindin IO, Farombi TH, Oladele JO, Izomoh ER, Aladelokun OB, et al. Neuroprotective role of kolaviron in striatal redo-inflammation associated with rotenone model of Parkinson’s disease. Neurotoxicology 2019; 73:132–141.
13. Nazari-Serenjeh M, Baluchnejadmojarad T, Hatami-Morassa M, Fahanik-Babaei J, Mehrabi S, Tashakori-Miyanroudi M, et al. Kolaviron neuroprotective effect against okadaic acid-provoked cognitive impairment. Heliyon 2024; 10:e25564.
14. Oyovwi MO, Ben-Azu B, Edesiri TP, Victor E, Rotu RA, Ozegbe QE, et al. Kolaviron abates busulfan-induced episodic memory deficit and testicular dysfunction in rats: the implications for neuroendopathobiological changes during chemotherapy. Biomed Pharmacother 2021; 142:112022.
15. Omotoso GO, Arietarhire LO, Ukwubile II, Gbadamosi IT. The protective effect of kolaviron on molecular, cellular, and behavioral characterization of cerebellum in the rat model of demyelinating diseases. Basic Clin Neurosci 2020; 11:609.
16. Omotoso GO, Mutholib NY, Abdulsalam FA , Bature AI. Kolaviron protects against cognitive deficits and cortico-hippocampal perturbations associated with maternal deprivation in rats. Anat Cell Biol 2019; 53:95.
17. Usui N, Kobayashi H, Shimada S. Neuroinflammation and oxidative stress in the pathogenesis of autism spectrum disorder. Int J Mol Sci 2023; 24:5487.
18. Muller CL, Anacker AMJ, Veenstra-VanderWeele J. The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience 2016; 321:24–41.
19. Afshari M, Gharibzadeh S, Pouretemad H, Roghani M. Reversing valproic acid-induced autism-like behaviors through a combination of low-frequency repeated transcranial magnetic stimulation and superparamagnetic iron oxide nanoparticles. Sci Rep 2024; 14:8082.
20. Zahedi E, Sadr SS, Sanaeierad A, Roghani M. Chronic acetyl-L-carnitine treatment alleviates behavioral deficits and neuroinflammation through enhancing microbiota derived-SCFA in valproate model of autism. Biomed Pharmacother 2023; 163:114848.
21. Feriyani F, Maulanza H, Lubis RR, Balqis U, Darmawi D. Effects of binahong (Anredera cordifolia (Tenore) Steenis) extracts on the levels of malondialdehyde (MDA) in cataract goat lenses. ScientificWorldJournal 2021; 2021:6617292.
22. Ghalami J, Baluchnejad Mojarad T, Mansouri M, Khamse S, Roghani M. Paeonol protection against intrastriatal 6-Hydroxydopamine rat model of parkinson’s disease. Basic Clin Neurosci 2021; 12:43–56.
23. Teixeira FC, Gutierres JM, Soares MSP, da Siveira de Mattos B, Spohr L, et al. Inosine protects against impairment of memory induced by experimental model of Alzheimer disease: a nucleoside with multitarget brain actions. Psychopharmacology (Berl) 2020; 237:811–823.
24. Ding J, Yu HL, Ma WW, Xi YD, Zhao X, Yuan LH, et al. Soy isoflavone attenuates brain mitochondrial oxidative stress induced by β-amyloid peptides 1-42 injection in lateral cerebral ventricle. J Neurosci Res 2013; 91:562–567.
25. Pourmohammadi S, Roghani M, Kiasalari Z, Khalili M. Paeonol ameliorates cuprizone-induced hippocampal demyelination and cognitive deficits through inhibition of oxidative and inflammatory events. J Mol Neurosci 2022; 72:748–758.
26. Olatoye FJ, Akindele AJ, Awodele O. The role of kolaviron, a bioflavonoid from Garcinia kola, in the management of cardiovascular diseases: A systematic review. Heliyon 2024; 10:e27333.
27. Tauchen J, Frankova A, Manourova A, Valterova I, Lojka B , Leuner O. Garcinia kola: A critical review on chemistry and pharmacology of an important West African medicinal plant. Phytochem Rev 2023:1–47.
28. Omotoso GO, Mutholib NY, Abdulsalam FA, Bature AI. Kolaviron protects against cognitive deficits and cortico-hippocampal perturbations associated with maternal deprivation in rats. Anat Cell Biol 2020; 53:95–106.
29. Chen S, Huang L, Liu G, Kang J, Qian Q, Wang J, et al. Acupuncture ameliorated behavioral abnormalities in the autism rat model via pathways for hippocampal serotonin. Neuropsychiatr Dis Treat 2023; 19:951–972.
30. Omotoso GO, Arietarhire LO, Ukwubile, II, Gbadamosi IT. The protective effect of kolaviron on molecular, cellular, and behavioral characterization of cerebellum in the rat model of demyelinating diseases. Basic Clin Neurosci 2020; 11:609–618.
31. Rahdar M, Davoudi S, Dehghan S, Javan M, Hosseinmardi N, Behzadi G, Janahmadi M. Reversal of electrophysiological and behavioral deficits mediated by 5-HT7 receptor upregulation following LP-211 treatment in an autistic-like rat model induced by prenatal valproic acid exposure. Neuropharmacology 2024; 257:110057.
32. Bristot Silvestrin R, Bambini-Junior V, Galland F, Daniele Bobermim L, Quincozes-Santos A, Torres Abib R, et al. Animal model of autism induced by prenatal exposure to valproate: Altered glutamate metabolism in the hippocampus. Brain Res 2013; 1495:52–60.
33. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005; 57:67–81.
34. Laurence JA, Fatemi SH. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum 2005; 4:206–210.
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 20 June 2026

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