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α-Linolenic acid ameliorates pentylenetetrazol-induced neuron apoptosis and neurological impairment in mice with seizures via down-regulating JAK2/STAT3 pathway

Published online by Cambridge University Press:  22 May 2024

Xin Zeng Open the ORCID record for Xin Zeng [Opens in a new window] ,
Fei Luo ,
Ya-hong Cheng ,
Jiefang Gao  and
Ding Hong
Xin Zeng
Affiliation:
Nanchong Key Laboratory of Individualized Drug Therapy, Department of Pharmacy, The Second Clinical Medical College of North Sichuan Medical College, Nanchong Central Hospital, Nanchong, People’s Republic of China
Fei Luo
Affiliation:
Department of Nuclear Medicine, The Affiliated Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China
Ya-hong Cheng
Affiliation:
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430000 Hubei, People’s Republic of China
Jiefang Gao
Affiliation:
Central Laboratory, the First Hospital of Hebei Medical University, Shijiazhuang 050031, Hebei Province, People’s Republic of China
Ding Hong*
Affiliation:
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430000 Hubei, People’s Republic of China
*
*Corresponding author: Ding Hong, email [email protected]
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Abstract

Epilepsy ranks fourth among neurological diseases, featuring spontaneous seizures and behavioural and cognitive impairments. Although anti-epileptic drugs are currently available clinically, 30 % of epilepsy patients are still ineffective in treatment and 52 % of patients experience serious adverse reactions. In this work, the neuroprotective effect of α-linolenic acid (ALA, a nutrient) in mice and its potential molecular mechanisms exposed to pentylenetetrazol (PTZ) was assessed. The mice were injected with pentetrazol 37 mg/kg, and ALA was intra-gastrically administered for 40 d. The treatment with ALA significantly reduced the overall frequency of epileptic seizures and improved the behaviour impairment and cognitive disorder caused by pentetrazol toxicity. In addition, ALA can not only reduce the apoptosis rate of brain neurons in epileptic mice but also significantly reduce the content of brain inflammatory factors (IL-6, IL-1 and TNF-α). Furthermore, we predicted that the possible targets of ALA in the treatment of epilepsy were JAK2 and STAT3 through molecular docking. Finally, through molecular docking and western blot studies, we revealed that the potential mechanism of ALA ameliorates PTZ-induced neuron apoptosis and neurological impairment in mice with seizures by down-regulating the JAK2/STAT3 pathway. This study aimed to investigate the anti-epileptic and neuroprotective effects of ALA, as well as explore its potential mechanisms, through the construction of a chronic ignition mouse model via intraperitoneal PTZ injection. The findings of this research provide crucial scientific support for subsequent clinical application studies in this field.

Keywords

α-Linolenic acidEpilepsyJAK2/STAT3 signalling pathwayNeuron apoptosisNeuroinflammationPentylenetetrazol toxicity
Type
Research Article
Information
British Journal of Nutrition , Volume 132 , Issue 1 , 14 July 2024 , pp. 1 - 12
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Copyright
© The Author(s), 2024. Published by Cambridge University Press on behalf of The Nutrition Society

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Footnotes

†

These authors contributed equally to this work.

References

Falco-Walter, J (2020) Epilepsy-definition, classification, pathophysiology, and epidemiology. Semin Neurol 40, 617–623.Google ScholarPubMed
Janmohamed, M, Brodie, MJ & Kwan, P (2020) Pharmacoresistance – epidemiology, mechanisms, and impact on epilepsy treatment. Neuropharmacol 168, 9.CrossRefGoogle ScholarPubMed
Yamashita, R, Takahashi, Y, Takashima, K, et al. (2021) Induction of cellular senescence as a late effect and BDNF-TrkB signaling-mediated ameliorating effect on disruption of hippocampal neurogenesis after developmental exposure to lead acetate in rats. Toxicology 456, 16.Google ScholarPubMed
Rezaie, M, Nasehi, M, Vaseghi, S, et al. (2020) The protective effect of α lipoic acid (ALA) on social interaction memory, but not passive avoidance in sleep-deprived rats. Naunyn-Schmiedeberg’s Arch Pharmacol 393, 2081–2091.CrossRefGoogle Scholar
Foster, VS, Rash, LD, King, GF, et al. (2021) Acid-sensing ion channels: expression and function in resident and infiltrating immune cells in the central nervous system. Front Cell Neurosci 15, 16.CrossRefGoogle ScholarPubMed
El-Gaphar, O, Abo-Youssef, AM & Halal, GK (2018) Levetiracetam mitigates lipopolysaccharide-induced JAK2/STAT3 and TLR4/MAPK signaling pathways activation in a rat model of adjuvant-induced arthritis. Eur J Pharmacol 826, 85–95.CrossRefGoogle Scholar
Xie, J, Li, YJ, Dai, JM, et al. (2019) Olfactory ensheathing cells grafted into the retina of RCS rats suppress inflammation by down-regulating the JAK/STAT pathway. Front Cell Neurosci 13, 18.CrossRefGoogle ScholarPubMed
Avila-Mendoza, J, Delgado-Rueda, K, Urban-Sosa, VA, et al. (2023) KLF13 regulates the activity of the GH-Induced JAK/STAT signaling by targeting genes involved in the pathway. Int J Mol Sci 24, 20.CrossRefGoogle ScholarPubMed
Li, Y, Zhang, L, Liu, Q, et al. (2020) The effect of single nucleotide polymorphisms of STAT3 on epilepsy in children. Eur Rev Med Pharmacol Sci 24, 837–842.Google ScholarPubMed
Guan, XF, Wang, Q, Liu, MX, et al. (2021) Possible involvement of the IL-6/JAK2/STAT3 pathway in the hypothalamus in depressive-like behavior of rats exposed to chronic mild stress. Neuropsychobiology 80, 279–287.CrossRefGoogle ScholarPubMed
Alhadidi, Q & Shah, ZA (2018) Cofilin mediates LPS-Induced microglial cell activation and associated neurotoxicity through activation of NF-kappa B and JAK-STAT pathway. Mol Neurobiol 55, 1676–1691.Google ScholarPubMed
Ahmed, MM, Carrel, AJ, Del Angel, YC, et al. (2021) Altered protein profiles during epileptogenesis in the pilocarpine mouse model of temporal lobe epilepsy. Front Neurol 12, 17.CrossRefGoogle ScholarPubMed
Che Has, AT (2023) The applications of the pilocarpine animal model of status epilepticus: 40 years of progress (1983–2023). Behav Brain Res 452, 114551.Google ScholarPubMed
Rebik, AA, Riga, VD, Smirnov, KS, et al. (2022) Social behavioral deficits in Krushinsky-Molodkina rats, an animal model of audiogenic epilepsy. J Pers Med 12, 2062.CrossRefGoogle Scholar
Arifin, WN & Zahiruddin, WM (2017) Sample size calculation in animal studies using resource equation approach. Malays J·Med Sci 24, 101–105.Google ScholarPubMed
Festing, MF (2018) On determining sample size in experiments involving laboratory animals. Lab·Anim 52, 341–350.Google ScholarPubMed
Zhou, Q, Zhu, S, Guo, Y, et al. (2018) Adenosine A1 receptors play an important protective role against cognitive impairment and long-term potentiation inhibition in a pentylenetetrazol mouse model of epilepsy. Mol Neurobiol 55, 3316–3327.CrossRefGoogle Scholar
Tasdemir, R & Colak, T (2021) Evaluation of subchronic formaldehyde exposure in rats with open field test. Int J Morphol 39, 1758–1762.CrossRefGoogle Scholar
Kraeuter, AK, Guest, PC & Sarnyai, Z (2019) The forced swim test for depression-like behavior in rodents. In Pre-Clinical Models: Techniques and Protocols, vol. 1916, pp. 75–80 [PC Guest, editor]. Totowa: Humana Press Inc.Google Scholar
Shao, S, Cui, Y, Chen, ZB, et al. (2020) Androgen deficit changes the response to antidepressant drugs in tail suspension test in mice. Aging Male 23, 1259–1265.CrossRefGoogle ScholarPubMed
Chernyuk, DP, Bol’shakova, AV, Vlasova, OL, et al. (2021) Possibilities and prospects of the behavioral test ‘Morris water maze’. J Evol Biochem Physiol 57, 289–303.Google Scholar
Hammitzsch, A, Chen, L, de Wit, J, et al. (2018) Inhibiting ex-vivo Th17 responses in Ankylosing Spondylitis by targeting Janus kinases. Sci Rep 8, 15645.CrossRefGoogle ScholarPubMed
Sexton, RE, Hachem, AH, Assi, AA, et al. (2018) Metabotropic glutamate receptor-1 regulates inflammation in triple negative breast cancer. Sci Rep 8, 16008.Google ScholarPubMed
Cao, Y, Ma, C & Zhu, JJ (2021) DNA technology-assisted signal amplification strategies in electrochemiluminescence bioanalysis. J Anal Test 5, 95–111.CrossRefGoogle Scholar
Zhang, C, Xin, H, Zhang, W, et al. (2016) CD5 binds to interleukin-6 and Induces a feed-forward loop with the transcription factor STAT3 in B cells to promote cancer. Immunity 44, 913–923.Google Scholar
Kikuchi, M, Takase, K, Hayakawa, M, et al. (2020) Altered behavior in mice overexpressing soluble ST2. Mol Brain 13, 74.Google ScholarPubMed
Pong, AW, Xu, KJ & Klein, P (2023) Recent advances in pharmacotherapy for epilepsy. Curr Opin Neurol 36, 77–85.CrossRefGoogle ScholarPubMed
Chen, ZP, Wang, S, Zhao, X, et al. (2023) Lipid-accumulated reactive astrocytes promote disease progression in epilepsy. Nat Neurosci 26, 542–554.CrossRefGoogle ScholarPubMed
Pan, H, Hu, XZ, Jacobowitz, DM, et al. (2012) Alpha-linolenic acid is a potent neuroprotective agent against soman-induced neuropathology. Neurotoxicol 33, 1219–1229.CrossRefGoogle ScholarPubMed
Pan, H, Piermartiri, TC, Chen, J, et al. (2015) Repeated systemic administration of the nutraceutical α-linolenic acid exerts neuroprotective efficacy, an antidepressant effect and improves cognitive performance when given after soman exposure. Neurotoxicol 51, 38–50.Google ScholarPubMed
McGonigal, A, Becker, C, Fath, J, et al. (2023) BDNF as potential biomarker of epilepsy severity and psychiatric comorbidity: pitfalls in the clinical population. Epilepsy Res 195, 107200.Google ScholarPubMed
Cheng, Y, Mai, Q, Zeng, X, et al. (2019) Propionate relieves pentylenetetrazol-induced seizures, consequent mitochondrial disruption, neuron necrosis and neurological deficits in mice. Biochem Pharmacol 169, 113607.Google ScholarPubMed
Blondeau, N, Nguemeni, C, Debruyne, DN, et al. (2009) Subchronic α-linolenic acid treatment enhances brain plasticity and exerts an antidepressant effect: a versatile potential therapy for stroke. Neuropsychopharmacol 34, 2548–2559.Google ScholarPubMed
Piermartiri, T, Pan, H, Figueiredo, TH, et al. (2015) α-linolenic acid, a nutraceutical with pleiotropic properties that targets endogenous neuroprotective pathways to protect against organophosphate nerve agent-induced neuropathology. Molecules (Basel, Switzerland) 20, 20355–20380.CrossRefGoogle ScholarPubMed
Piermartiri, TC, Pan, H, Chen, J, et al. (2015) Alpha-linolenic acid-induced increase in neurogenesis is a key factor in the improvement in the passive avoidance task after soman exposure. Neuromolecular Med 17, 251–269.Google ScholarPubMed
Dey, A, Kang, X, Qiu, J, et al. (2016) Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside. Trends Pharmacol Sci 37, 463–484.Google ScholarPubMed
Kra, G, Daddam, JR, Moallem, U, et al. (2023) Alpha-linolenic acid modulates systemic and adipose tissue-specific insulin sensitivity, inflammation, and the endocannabinoid system in dairy cows. Sci Rep 13, 5280.Google ScholarPubMed
Cambiaggi, L, Chakravarty, A, Noureddine, N, et al. (2023) The role of α-linolenic acid and its oxylipins in human cardiovascular diseases. Int J Mol Sci 24, 6110.CrossRefGoogle ScholarPubMed
van Vliet, EA, Aronica, E, Vezzani, A, et al. (2018) Review: neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies. Neuropathol Appl Neurobiol 44, 91–111.Google ScholarPubMed
Wang, Q & Wang, X (2023) The effects of a low linoleic acid/α-linolenic acid ratio on lipid metabolism and endogenous fatty acid distribution in obese mice. Int J Mol Sci 24, 12117.CrossRefGoogle ScholarPubMed
Li, C, Wang, RL, Zhang, YY, et al. (2021) PIAS3 suppresses damage in an Alzheimer’s disease cell model by inducing the STAT3-associated STAT3/Nestin/Nrf2/HO-1 pathway. Mol Med 27, 13.CrossRefGoogle Scholar
Ni, H, Liao, Y, Zhang, Y, et al. (2023) Levistilide A ameliorates neuroinflammation via inhibiting JAK2/STAT3 signaling for neuroprotection and cognitive improvement in scopolamine-induced Alzheimer’s disease mouse model. Int Immunopharmacol 124, 110783.CrossRefGoogle ScholarPubMed
Zhang, W, Xu, M, Chen, F, et al. (2023) Targeting the JAK2-STAT3 pathway to inhibit cGAS-STING activation improves neuronal senescence after ischemic stroke. Exp Neurol 368, 114474.CrossRefGoogle ScholarPubMed
Kong, XJ, Gong, Z, Zhang, L, et al. (2019) JAK2/STAT3 signaling mediates IL-6-inhibited neurogenesis of neural stem cells through DNA demethylation/methylation. Brain Behav Immun 79, 159–173.CrossRefGoogle ScholarPubMed
Rabie, MA, Fattah, MAA, Nassar, NN, et al. (2020) Correlation between angiotensin 1–7-mediated Mas receptor expression with motor improvement, activated STAT3/SOCS3 cascade, and suppressed HMGB-1/RAGE/NF-kappa B signaling in 6-hydroxydopamine hemiparkinsonian rats. Biochem Pharmacol 171, 9.CrossRefGoogle ScholarPubMed
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