Research Article

IC87201, a PSD-95/nNOS Inhibitor, Ameliorates Heart Rate Variability in the Rat Model of Middle Cerebral Artery Occlusion

Maryam Mohammadian and Aminollah Bahaoddini*

Published: 11 July, 2023 | Volume 7 - Issue 1 | Pages: 001-006

Objective: Assessment of heart rate variability (HRV) is a non-invasive and reliable method to evaluate autonomic disorders after cerebral ischemia. The present study was conducted to investigate the therapeutic potential of IC87201 in reducing post-stroke cardiac dysfunction. 
Materials and methods: Cerebral ischemia was induced by the middle cerebral artery occlusion (MCAO) method in 15 anesthetized adult male rats in three MCAO, MCAO+ DXM, and MCAO+ IC87201 groups, for one hour. Electrocardiogram was recorded before, and 48 hours after ischemia and drug administration, and HRV parameters were calculated from R-R intervals. In the treatment groups, IC87201 and Dextromethorphan hydrobromide monohydrate (DXM) were injected after an ischemic period. 
Results: After brain ischemia, the R-R interval decreased and consequently heart rate increased. The R-R intervals were used to extract the HRV frequency and time domains, including normalized low frequency (LF), high frequency (HF), LF/HF ratio, and standard deviation of R-R interval (SDRR). Normalized LF and LF/HF ratio enhanced 48 hours after ischemia, while normalized HF and SDRR significantly reduced compared to the pre-ischemic state. All HRV parameters had returned to their pre-ischemic level 48 hours after IC87201 and DXM administration, except SDRR, which recovered only in the IC87201 administered group. 
Conclusion: Based on our findings, it can be concluded that cerebral ischemia significantly worsens HRV parameters as a result of sympathetic overactivity. These changes were reversed by administering DXM and IC87201, but IC87201 has generally been more effective in lowering lesions. As a result, IC87201 can be introduced as an effective substance for the treatment of post-ischemic cardiac side effects.

Read Full Article HTML DOI: 10.29328/journal.ibm.1001024 Cite this Article Read Full Article PDF


Cerebral ischemia; Heart rate variability; IC87201; Middle cerebral artery occlusion; Stroke


  1. Wu QJ, Tymianski M. Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain. 2018 Mar 13;11(1):15. doi: 10.1186/s13041-018-0357-8. PMID: 29534733; PMCID: PMC5851248.
  2. Barthels D, Das H. Current advances in ischemic stroke research and therapies. Biochim Biophys Acta Mol Basis Dis. 2020 Apr 1;1866(4):165260. doi: 10.1016/j.bbadis.2018.09.012. Epub 2018 Sep 15. PMID: 31699365; PMCID: PMC6981280.
  3. Grysiewicz RA, Thomas K, Pandey DK. Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin. 2008 Nov;26(4):871-95, vii. doi: 10.1016/j.ncl.2008.07.003. PMID: 19026895.
  4. Prosser J, MacGregor L, Lees KR, Diener HC, Hacke W, Davis S; VISTA Investigators. Predictors of early cardiac morbidity and mortality after ischemic stroke. Stroke. 2007 Aug;38(8):2295-302. doi: 10.1161/STROKEAHA.106.471813. Epub 2007 Jun 14. PMID: 17569877.
  5. Chen CF, Lin HF, Lin RT, Yang YH, Lai CL. Relationship between ischemic stroke location and autonomic cardiac function. J Clin Neurosci. 2013 Mar;20(3):406-9. doi: 10.1016/j.jocn.2012.02.047. Epub 2012 Dec 7. PMID: 23219823.
  6. Manea MM, Comsa M, Minca A, Dragos D, Popa C. Brain-heart axis--Review Article. J Med Life. 2015 Jul-Sep;8(3):266-71. PMID: 26351525; PMCID: PMC4556904.
  7. Buitrago-Ricaurte N, Cintra F, Silva GS. Heart rate variability as an autonomic biomarker in ischemic stroke. Arq Neuropsiquiatr. 2020 Nov;78(11):724-732. doi: 10.1590/0004-282X20200087. PMID: 33331466.
  8. Singh N, Moneghetti KJ, Christle JW, Hadley D, Froelicher V, Plews D. Heart Rate Variability: An Old Metric with New Meaning in the Era of Using mHealth technologies for Health and Exercise Training Guidance. Part Two: Prognosis and Training. Arrhythm Electrophysiol Rev. 2018 Dec;7(4):247-255. doi: 10.15420/aer.2018.30.2. PMID: 30588312; PMCID: PMC6304793.
  9. Guan L, Collet JP, Mazowita G, Claydon VE. Autonomic Nervous System and Stress to Predict Secondary Ischemic Events after Transient Ischemic Attack or Minor Stroke: Possible Implications of Heart Rate Variability. Front Neurol. 2018 Mar 5;9:90. doi: 10.3389/fneur.2018.00090. PMID: 29556209; PMCID: PMC5844932.
  10. Sörös P, Hachinski V. Cardiovascular and neurological causes of sudden death after ischaemic stroke. Lancet Neurol. 2012 Feb;11(2):179-88. doi: 10.1016/S1474-4422(11)70291-5. PMID: 22265213.
  11. Colivicchi F, Bassi A, Santini M, Caltagirone C. Cardiac autonomic derangement and arrhythmias in right-sided stroke with insular involvement. Stroke. 2004 Sep;35(9):2094-8. doi: 10.1161/01.STR.0000138452.81003.4c. Epub 2004 Jul 22. PMID: 15272134.
  12. Colivicchi F, Bassi A, Santini M, Caltagirone C. Prognostic implications of right-sided insular damage, cardiac autonomic derangement, and arrhythmias after acute ischemic stroke. Stroke. 2005 Aug;36(8):1710-5. doi: 10.1161/01.STR.0000173400.19346.bd. Epub 2005 Jul 14. PMID: 16020766.
  13. Fyfe-Johnson AL, Muller CJ, Alonso A, Folsom AR, Gottesman RF, Rosamond WD, Whitsel EA, Agarwal SK, MacLehose RF. Heart Rate Variability and Incident Stroke: The Atherosclerosis Risk in Communities Study. Stroke. 2016 Jun;47(6):1452-8. doi: 10.1161/STROKEAHA.116.012662. Epub 2016 May 5. PMID: 27217501; PMCID: PMC4880420.
  14. Huikuri HV, Stein PK. Heart rate variability in risk stratification of cardiac patients. Prog Cardiovasc Dis. 2013 Sep-Oct;56(2):153-9. doi: 10.1016/j.pcad.2013.07.003. Epub 2013 Aug 12. PMID: 24215747.
  15. Yperzeele L, van Hooff RJ, Nagels G, De Smedt A, De Keyser J, Brouns R. Heart rate variability and baroreceptor sensitivity in acute stroke: a systematic review. Int J Stroke. 2015 Aug;10(6):796-800. doi: 10.1111/ijs.12573. PMID: 26202709.
  16. Bodapati RK, Kizer JR, Kop WJ, Kamel H, Stein PK. Addition of 24-Hour Heart Rate Variability Parameters to the Cardiovascular Health Study Stroke Risk Score and Prediction of Incident Stroke: The Cardiovascular Health Study. J Am Heart Assoc. 2017 Jul 21;6(7):e004305. doi: 10.1161/JAHA.116.004305. PMID: 28733431; PMCID: PMC5586256.
  17. Albers GW, Atkinson RP, Kelley RE, Rosenbaum DM. Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group. Stroke. 1995 Feb;26(2):254-8. doi: 10.1161/01.str.26.2.254. PMID: 7831698.
  18. Diener HC, AlKhedr A, Busse O, Hacke W, Zingmark PH, Jonsson N, Basun H; Study group. Treatment of acute ischaemic stroke with the low-affinity, use-dependent NMDA antagonist AR-R15896AR. A safety and tolerability study. J Neurol. 2002 May;249(5):561-8. doi: 10.1007/s004150200065. PMID: 12021946.
  19. Grotta J, Clark W, Coull B, Pettigrew LC, Mackay B, Goldstein LB, Meissner I, Murphy D, LaRue L. Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial. Stroke. 1995 Apr;26(4):602-5. doi: 10.1161/01.str.26.4.602. PMID: 7709405.
  20. Wood PL, Hawkinson JE. N-methyl-D-aspartate antagonists for stroke and head trauma. Expert Opin Investig Drugs. 1997 Apr;6(4):389-97. doi: 10.1517/13543784.6.4.389. PMID: 15989606.
  21. Florio SK, Loh C, Huang SM, Iwamaye AE, Kitto KF, Fowler KW, Treiberg JA, Hayflick JS, Walker JM, Fairbanks CA, Lai Y. Disruption of nNOS-PSD95 protein-protein interaction inhibits acute thermal hyperalgesia and chronic mechanical allodynia in rodents. Br J Pharmacol. 2009 Sep;158(2):494-506. doi: 10.1111/j.1476-5381.2009.00300.x. PMID: 19732061; PMCID: PMC2757689.
  22. Lee WH, Xu Z, Ashpole NM, Hudmon A, Kulkarni PM, Thakur GA, Lai YY, Hohmann AG. Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics. Neuropharmacology. 2015 Oct;97:464-75. doi: 10.1016/j.neuropharm.2015.05.038. Epub 2015 Jun 10. PMID: 26071110; PMCID: PMC4539046.
  23. Zhou L, Li F, Xu HB, Luo CX, Wu HY, Zhu MM, Lu W, Ji X, Zhou QG, Zhu DY. Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95. Nat Med. 2010 Dec;16(12):1439-43. doi: 10.1038/nm.2245. Epub 2010 Nov 21. Erratum in: Nat Med. 2011 Sep;17(9):1153. PMID: 21102461.
  24. Owjfard M, Bigdeli MR, Safari A, Namavar MR. Effects of nicorandil on neurobehavioral function, BBB integrity, edema and stereological parameters of the brain in the sub-acute phase of stroke in a rat model. J Biosci. 2020;45:49. PMID: 32345775.
  25. Naderi Y, Sabetkasaei M, Parvardeh S, Moini Zanjani T. Neuroprotective effects of pretreatment with minocycline on memory impairment following cerebral ischemia in rats. Behav Pharmacol. 2017 Apr;28(2 and 3-Spec Issue):214-222. doi: 10.1097/FBP.0000000000000297. PMID: 28257293.
  26. Smith AE, Xu Z, Lai YY, Kulkarni PM, Thakur GA, Hohmann AG, Crystal JD. Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein-protein interaction inhibitors. Behav Brain Res. 2016 May 15;305:23-9. doi: 10.1016/j.bbr.2016.02.021. Epub 2016 Feb 22. PMID: 26909849; PMCID: PMC4808404.
  27. Bokesch PM, Marchand JE, Connelly CS, Wurm WH, Kream RM. Dextromethorphan inhibits ischemia-induced c-fos expression and delayed neuronal death in hippocampal neurons. Anesthesiology. 1994 Aug;81(2):470-7. doi: 10.1097/00000542-199408000-00026. PMID: 8053597.
  28. Verma AK, Aarotale PN, Dehkordi P, Lou JS, Tavakolian K. Relationship between Ischemic Stroke and Pulse Rate Variability as a Surrogate of Heart Rate Variability. Brain Sci. 2019 Jul 10;9(7):162. doi: 10.3390/brainsci9070162. PMID: 31295816; PMCID: PMC6680838.
  29. Meyer S, Strittmatter M, Fischer C, Georg T, Schmitz B. Lateralization in autonomic dysfunction in ischemic stroke involving the insular cortex. Neuroreport. 2004 Feb 9;15(2):357-61. doi: 10.1097/00001756-200402090-00029. PMID: 15076768.
  30. Shaffer F, Ginsberg JP. An Overview of Heart Rate Variability Metrics and Norms. Front Public Health. 2017 Sep 28;5:258. doi: 10.3389/fpubh.2017.00258. PMID: 29034226; PMCID: PMC5624990.
  31. Oka H. Heart rate variability and neurological disorders. Clinical assessment of the autonomic nervous system. 2017; 179-197.
  32. Ay H, Koroshetz WJ, Benner T, Vangel MG, Melinosky C, Arsava EM, Ayata C, Zhu M, Schwamm LH, Sorensen AG. Neuroanatomic correlates of stroke-related myocardial injury. Neurology. 2006 May 9;66(9):1325-9. doi: 10.1212/01.wnl.0000206077.13705.6d. Epub 2006 Mar 8. PMID: 16525122.
  33. Dütsch M, Burger M, Dörfler C, Schwab S, Hilz MJ. Cardiovascular autonomic function in poststroke patients. Neurology. 2007 Dec 11;69(24):2249-55. doi: 10.1212/01.wnl.0000286946.06639.a7. PMID: 18071145.
  34. Chevalier G, Sinatra ST. Emotional stress, heart rate variability, grounding, and improved autonomic tone: clinical applications. Integrative Medicine. 2011; 10(3): 16-21.
  35. Marins FR, Iddings JA, Fontes MA, Filosa JA. Evidence that remodeling of insular cortex neurovascular unit contributes to hypertension-related sympathoexcitation. Physiol Rep. 2017 Mar;5(5):e13156. doi: 10.14814/phy2.13156. PMID: 28270592; PMCID: PMC5350170.
  36. Walter U, Kolbaske S, Patejdl R, Steinhagen V, Abu-Mugheisib M, Grossmann A, Zingler C, Benecke R. Insular stroke is associated with acute sympathetic hyperactivation and immunodepression. Eur J Neurol. 2013 Jan;20(1):153-9. doi: 10.1111/j.1468-1331.2012.03818.x. Epub 2012 Jul 27. PMID: 22834894.
  37. Micieli G, Cavallini A. The autonomic nervous system and ischemic stroke: a reciprocal interdependence. Clin Auton Res. 2008 Dec;18(6):308-17. doi: 10.1007/s10286-008-0495-7. Epub 2008 Oct 11. PMID: 18850312.
  38. Werling LL, Lauterbach EC, Calef U. Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action. Neurologist. 2007 Sep;13(5):272-93. doi: 10.1097/NRL.0b013e3180f60bd8. PMID: 17848867.
  39. Fink JN, Selim MH, Kumar S, Voetsch B, Fong WC, Caplan LR. Insular cortex infarction in acute middle cerebral artery territory stroke: predictor of stroke severity and vascular lesion. Arch Neurol. 2005 Jul;62(7):1081-5. doi: 10.1001/archneur.62.7.1081. PMID: 16009763.
  40. Marins FR, Limborço-Filho M, Iddings JA, Xavier CH, Biancardi VC, Stern JE, Ramiro Diaz J, Oppenheimer SM, Filosa JA, Peliky Fontes MA. Tachycardia evoked from insular stroke in rats is dependent on glutamatergic neurotransmission in the dorsomedial hypothalamus. Eur J Neurol. 2021 Nov;28(11):3640-3649. doi: 10.1111/ene.14987. Epub 2021 Jul 9. PMID: 34152065.


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