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Published in: Neuroscience Bulletin 5/2024

16-11-2023 | Dextromethorphan | Original Article

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

Authors: Jing-Jing Yang, Ying-Xin Liu, Yan-Fang Wang, Bi-Ying Ge, Ying Wang, Qing-Shan Wang, Sheng Li, Jian-Jie Zhang, Ling-Ling Jin, Jau-Shyong Hong, Sheng-Ming Yin, Jie Zhao

Published in: Neuroscience Bulletin | Issue 5/2024

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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.
Literature
1.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
2.
go back to reference Marcangelo MJ, Ovsiew F. Psychiatric aspects of epilepsy. Psychiatr Clin North Am 2007, 30: 781–802.PubMedCrossRef Marcangelo MJ, Ovsiew F. Psychiatric aspects of epilepsy. Psychiatr Clin North Am 2007, 30: 781–802.PubMedCrossRef
3.
4.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
5.
go back to reference Waldbaum S, Patel M. Mitochondrial dysfunction and oxidative stress: A contributing link to acquired epilepsy? J Bioenerg Biomembr 2010, 42: 449–455.PubMedPubMedCentralCrossRef Waldbaum S, Patel M. Mitochondrial dysfunction and oxidative stress: A contributing link to acquired epilepsy? J Bioenerg Biomembr 2010, 42: 449–455.PubMedPubMedCentralCrossRef
6.
go back to reference Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology 2013, 69: 16–24.PubMedCrossRef Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology 2013, 69: 16–24.PubMedCrossRef
7.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
9.
go back to reference Liang LP, Ho YS, Patel M. Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 2000, 101: 563–570.PubMedCrossRef Liang LP, Ho YS, Patel M. Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 2000, 101: 563–570.PubMedCrossRef
10.
go back to reference Patel M, Day BJ, Crapo JD, Fridovich I, McNamara JO. Requirement for superoxide in excitotoxic cell death. Neuron 1996, 16: 345–355.PubMedCrossRef Patel M, Day BJ, Crapo JD, Fridovich I, McNamara JO. Requirement for superoxide in excitotoxic cell death. Neuron 1996, 16: 345–355.PubMedCrossRef
11.
go back to reference Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 2004, 3: 205–214.PubMedCrossRef Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 2004, 3: 205–214.PubMedCrossRef
12.
go back to reference Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 2007, 87: 245–313.PubMedCrossRef Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 2007, 87: 245–313.PubMedCrossRef
13.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
14.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
15.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
16.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
17.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
18.
19.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
20.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
21.
22.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
23.
go back to reference Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972, 32: 281–294.PubMedCrossRef Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972, 32: 281–294.PubMedCrossRef
24.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
25.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
26.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
27.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
28.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
29.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
30.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
31.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
32.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
33.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
34.
go back to reference 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.PubMed 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.PubMed
35.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
36.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
37.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
38.
go back to reference 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.PubMedPubMedCentralCrossRef 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.PubMedPubMedCentralCrossRef
39.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
40.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
41.
go back to reference Ferkany JW, Borosky SA, Clissold DB, Pontecorvo MJ. Dextromethorphan inhibits NMDA-induced convulsions. Eur J Pharmacol 1988, 151: 151–154.PubMedCrossRef Ferkany JW, Borosky SA, Clissold DB, Pontecorvo MJ. Dextromethorphan inhibits NMDA-induced convulsions. Eur J Pharmacol 1988, 151: 151–154.PubMedCrossRef
42.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
43.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
Metadata
Title
Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats
Authors
Jing-Jing Yang
Ying-Xin Liu
Yan-Fang Wang
Bi-Ying Ge
Ying Wang
Qing-Shan Wang
Sheng Li
Jian-Jie Zhang
Ling-Ling Jin
Jau-Shyong Hong
Sheng-Ming Yin
Jie Zhao
Publication date
16-11-2023
Publisher
Springer Nature Singapore
Published in
Neuroscience Bulletin / Issue 5/2024
Print ISSN: 1673-7067
Electronic ISSN: 1995-8218
DOI
https://doi.org/10.1007/s12264-023-01140-8

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