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Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats

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Abstract

Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy (TLE). We postulated that kainic acid (KA)-Induced status epilepticus triggers microglia-dependent inflammation, leading to neuronal damage, a lowered seizure threshold, and the emergence of spontaneous recurrent seizures (SRS). Extensive evidence from our laboratory suggests that dextromethorphan (DM), even in ultra-low doses, has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease. Our results showed that administration of DM (10 ng/kg per day; subcutaneously via osmotic minipump for 4 weeks) significantly mitigated the residual effects of KA, including the frequency of SRS and seizure susceptibility. In addition, DM-treated rats showed improved cognitive function and reduced hippocampal neuronal loss. We found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91phox and p47phox proteins in KA-induced chronic TLE rats. Notably, even after discontinuation of DM treatment, ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects, which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.

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References

  1. Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR. Estimation of the burden of active and life-time epilepsy: A meta-analytic approach. Epilepsia 2010, 51: 883–890.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Marcangelo MJ, Ovsiew F. Psychiatric aspects of epilepsy. Psychiatr Clin North Am 2007, 30: 781–802.

    Article  PubMed  Google Scholar 

  3. Devinsky O, Spruill T, Thurman D, Friedman D. Recognizing and preventing epilepsy-related mortality: A call for action. Neurology 2016, 86: 779–786.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Galanopoulou AS, Buckmaster PS, Staley KJ, Moshé SL, Perucca E, Engel J Jr. Identification of new epilepsy treatments: Issues in preclinical methodology. Epilepsia 2012, 53: 571–582.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Waldbaum S, Patel M. Mitochondrial dysfunction and oxidative stress: A contributing link to acquired epilepsy? J Bioenerg Biomembr 2010, 42: 449–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology 2013, 69: 16–24.

    Article  CAS  PubMed  Google Scholar 

  7. Pecorelli A, Natrella F, Belmonte G, Miracco C, Cervellati F, Ciccoli L, et al. NADPH oxidase activation and 4-hydroxy-2-nonenal/aquaporin-4 adducts as possible new players in oxidative neuronal damage presents in drug-resistant epilepsy. Biochim Biophys Acta 2015, 1852: 507–519.

    Article  CAS  PubMed  Google Scholar 

  8. Singh PK, Saadi A, Sheeni Y, Shekh-Ahmad T. Specific inhibition of NADPH oxidase 2 modifies chronic epilepsy. Redox Biol 2022, 58: 102549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Liang LP, Ho YS, Patel M. Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 2000, 101: 563–570.

    Article  CAS  PubMed  Google Scholar 

  10. Patel M, Day BJ, Crapo JD, Fridovich I, McNamara JO. Requirement for superoxide in excitotoxic cell death. Neuron 1996, 16: 345–355.

    Article  CAS  PubMed  Google Scholar 

  11. Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 2004, 3: 205–214.

    Article  CAS  PubMed  Google Scholar 

  12. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 2007, 87: 245–313.

    Article  CAS  PubMed  Google Scholar 

  13. Kim JH, Jang BG, Choi BY, Kim HS, Sohn M, Chung TN, et al. Post-treatment of an NADPH oxidase inhibitor prevents seizure-induced neuronal death. Brain Res 2013, 1499: 163–172.

    Article  CAS  PubMed  Google Scholar 

  14. Huang WY, Lin S, Chen HY, Chen YP, Chen TY, Hsu KS, et al. NADPH oxidases as potential pharmacological targets against increased seizure susceptibility after systemic inflammation. J Neuroinflammation 2018, 15: 140.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chechneva OV, Mayrhofer F, Daugherty DJ, Pleasure DE, Hong JS, Deng W. Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. Neurobiol Dis 2011, 44: 63–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang W, Wang T, Qin L, Gao HM, Wilson B, Ali SF, et al. Neuroprotective effect of dextromethorphan in the MPTP Parkinson’s disease model: Role of NADPH oxidase. FASEB J 2004, 18: 589–591.

    Article  CAS  PubMed  Google Scholar 

  17. Li G, Cui G, Tzeng NS, Wei SJ, Wang T, Block ML, et al. Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage. FASEB J 2005, 19: 489–496.

    Article  CAS  PubMed  Google Scholar 

  18. Liu ES, Chen NC, Jao TM, Chen CL. Dextromethorphan reduces oxidative stress and inhibits uremic artery calcification. Int J Mol Sci 2021, 22: 12277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou R, Chen SH, Li G, Chen HL, Liu Y, Wu HM, et al. Ultralow doses of dextromethorphan protect mice from endotoxin-induced sepsis-like hepatotoxicity. Chem Biol Interact 2019, 303: 50–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gano LB, Liang LP, Ryan K, Michel CR, Gomez J, Vassilopoulos A, et al. Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy. Free Radic Biol Med 2018, 123: 116–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liang LP, Patel M. Plasma cysteine/cystine redox couple disruption in animal models of temporal lobe epilepsy. Redox Biol 2016, 9: 45–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sharma S, Puttachary S, Thippeswamy A, Kanthasamy AG, Thippeswamy T. Status epilepticus: Behavioral and electroencephalography seizure correlates in kainate experimental models. Front Neurol 2018, 9: 7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972, 32: 281–294.

    Article  CAS  PubMed  Google Scholar 

  24. Szot P, Weinshenker D, White SS, Robbins CA, Rust NC, Schwartzkroin PA, et al. Norepinephrine-deficient mice have increased susceptibility to seizure-inducing stimuli. J Neurosci 1999, 19: 10985–10992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Galic MA, Riazi K, Heida JG, Mouihate A, Fournier NM, Spencer SJ, et al. Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci 2008, 28: 6904–6913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu XM, Browning J, Liao Z, Cao Y, Yang W, Shear DA. Post-traumatic epilepsy and seizure susceptibility in rat models of penetrating and closed-head brain injury. J Neurotrauma 2020, 37: 236–247.

    Article  PubMed  Google Scholar 

  27. Feng XY, Hu HD, Chen J, Long C, Yang L, Wang L. Acute neuroinflammation increases excitability of prefrontal parvalbumin interneurons and their functional recruitment during novel object recognition. Brain Behav Immun 2021, 98: 48–58.

    Article  CAS  PubMed  Google Scholar 

  28. Becker I, Wang-Eckhardt L, Lodder-Gadaczek J, Wang Y, Grünewald A, Eckhardt M. Mice deficient in the NAAG synthetase II gene Rimkla are impaired in a novel object recognition task. J Neurochem 2021, 157: 2008–2023.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang X, Xue Y, Li J, Xu H, Yan W, Zhao Z, et al. The involvement of ADAR1 in antidepressant action by regulating BDNF via miR-432. Behav Brain Res 2021, 402: 113087.

    Article  CAS  PubMed  Google Scholar 

  30. Arabadzisz D, Antal K, Parpan F, Emri Z, Fritschy JM. Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus. Exp Neurol 2005, 194: 76–90.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang X, Tu D, Li S, Li N, Li D, Gao Y, et al. A novel synthetic peptide SVHRSP attenuates dopaminergic neurodegeneration by inhibiting NADPH oxidase-mediated neuroinflammation in experimental models of Parkinson’s disease. Free Radic Biol Med 2022, 188: 363–374.

    Article  CAS  PubMed  Google Scholar 

  32. Wang Y, Liu Y, Zhao Z, Wu X, Lin J, Li Y, et al. The involvement of ADAR1 in chronic unpredictable stress-induced cognitive impairment by targeting DARPP-32 with miR-874-3p in BALB/c mice. Front Cell Dev Biol 2023, 11: 919297.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bing G, Wilson B, Hudson P, Jin L, Feng Z, Zhang W, et al. A single dose of kainic acid elevates the levels of enkephalins and activator protein-1 transcription factors in the hippocampus for up to 1 year. Proc Natl Acad Sci U S A 1997, 94: 9422–9427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim HC, Pennypacker KR, Bing G, Bronstein D, McMillian MK, Hong JS. The effects of dextromethorphan on kainic acid-induced seizures in the rat. Neurotoxicology 1996, 17: 375–385.

    CAS  PubMed  Google Scholar 

  35. Pérez-Otano I, McMillian MK, Chen J, Bing G, Hong JS, Pennypacker KR. Induction of NF-kB-like transcription factors in brain areas susceptible to kainate toxicity. Glia 1996, 16: 306–315.

    Article  PubMed  Google Scholar 

  36. Wang Q, Qian L, Chen SH, Chu CH, Wilson B, Oyarzabal E, et al. Post-treatment with an ultra-low dose of NADPH oxidase inhibitor diphenyleneiodonium attenuates disease progression in multiple Parkinson’s disease models. Brain 2015, 138: 1247–1262.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Tsai RY, Jang FL, Tai YH, Lin SL, Shen CH, Wong CS. Ultra-low-dose naloxone restores the antinociceptive effect of morphine and suppresses spinal neuroinflammation in PTX-treated rats. Neuropsychopharmacology 2008, 33: 2772–2782.

    Article  CAS  PubMed  Google Scholar 

  38. Nitzan K, Ellenbogen L, Bentulila Z, David D, Franko M, Break EP, et al. An ultra-low dose of ∆9-tetrahydrocannabinol alleviates alzheimer’s disease-related cognitive impairments and modulates TrkB receptor expression in a 5XFAD mouse model. Int J Mol Sci 2022, 23: 9449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Taylor CP, Traynelis SF, Siffert J, Pope LE, Matsumoto RR. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther 2016, 164: 170–182.

    Article  CAS  PubMed  Google Scholar 

  40. Mohseni G, Ostadhadi S, Akbarian R, Chamanara M, Norouzi-Javidan A, Dehpour AR. Anticonvulsant effect of dextrometrophan on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide and N-methyl-d-aspartate receptors. Epilepsy Behav 2016, 65: 49–55.

    Article  PubMed  Google Scholar 

  41. Ferkany JW, Borosky SA, Clissold DB, Pontecorvo MJ. Dextromethorphan inhibits NMDA-induced convulsions. Eur J Pharmacol 1988, 151: 151–154.

    Article  CAS  PubMed  Google Scholar 

  42. Kim HC, Ko KH, Kim WK, Shin EJ, Kang KS, Shin CY, et al. Effects of dextromethorphan on the seizures induced by kainate and the calcium channel agonist BAY k-8644: Comparison with the effects of dextrorphan. Behav Brain Res 2001, 120: 169–175.

    Article  CAS  PubMed  Google Scholar 

  43. Kim HC, Bing G, Jhoo WK, Kim WK, Shin EJ, Im DH, et al. Metabolism to dextrorphan is not essential for dextromethorphan’s anticonvulsant activity against kainate in mice. Life Sci 2003, 72: 769–783.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Major Scientific and Technological Special Project for Significant New Drugs Development (2019zx09301102); the Project of Liaoning Provincial Department of Education (LJKZ0826) and the Open Project of National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases (2022GCYJZX-YB02).

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  1. Jing-Jing Yang, Ying-Xin Liu, and Yan-Fang Wang contributed equally to this work.

Authors and Affiliations

  1. College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China

    Jing-Jing Yang, Ying-Xin Liu, Yan-Fang Wang, Sheng Li, Jian-Jie Zhang, Sheng-Ming Yin & Jie Zhao

  2. Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China

    Jing-Jing Yang, Ying Wang & Jian-Jie Zhang

  3. National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases, Dalian, 116044, China

    Jing-Jing Yang, Ying-Xin Liu, Yan-Fang Wang, Bi-Ying Ge, Qing-Shan Wang, Sheng Li, Ling-Ling Jin, Sheng-Ming Yin & Jie Zhao

  4. School of Public Health, Dalian Medical University, Dalian, 116044, China

    Qing-Shan Wang

  5. Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC, 27709, USA

    Jau-Shyong Hong

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Yang, JJ., Liu, YX., Wang, YF. et al. Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats. Neurosci. Bull. (2023). https://doi.org/10.1007/s12264-023-01140-8

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