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Neurokinin-1 receptor inhibition reverses ischaemic brain injury and dementia in bilateral common carotid artery occluded rats: possible mechanisms

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Abstract

Backgrounds

Increase in SP release as a function of hypoxia of the rat carotid body is a tissue response to ischemia that leads to neurogenic inflammation and cognitive deficits. Substance P-mediated inflammation is reported to attenuate the neuroprotective PPAR-γ. This study was undertaken to investigate the effect of aprepitant, a substance P-NK1 receptor antagonist in bilateral carotid artery occlusion (BCCAO)-induced ischaemic brain injury and vascular dementia.

Methods

Bilateral carotid artery occlusion was performed in Wistar rats to produce hypoperfusion and ischaemic injury. Dementia was noted by an increase in brain acetylcholinesterase (AChE) activity, and attenuation of learning ability (escape latency time) and memory retention (time spent in target quadrant) using Morris water maze. Oxidative stress was estimated by an increase in thiobarbituric acid reactive substances (TBARS) level and a decrease in reduced glutathione level. Vascular dysfunction was measured by attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated carotid ring preparation), and increased in carotid artery TBARS level. Neurodegeneration was assessed in the hippocampus by H&E staining. Aprepitant and donepezil (positive control) were administered to rats from day 28 to day 42 after BCCAO.

Results

Aprepitant (20 and 40 mg/kg) and donepezil (2 mg/kg) significantly improved vascular function, learning and memory ability, and decreases the neuronal cell death, oxidative stress, and ache in BCCAO rats. Donepezil effect was more significant than the low dose of aprepitant on disease markers. However, BADGE (30 mg/kg a, PPAR-γ antagonist) prevented the ameliorative effect of aprepitant.

Conclusion

Thus, it may be concluded that aprepitant attenuates vascular dysfunction and dementia in BCCAO rats by activating downstream PPAR-γ.

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References

  • Biradar SM, Joshi H, Chheda TK (2014) Biochanin-A ameliorates behavioral and neurochemical derangements in cognitive-deficit mice for the betterment of Alzheimer’s disease. Hum Exp Toxicol 33:369–382

    Article  CAS  PubMed  Google Scholar 

  • Clark RB (2002) The role of PPARs in inflammation and immunity. J Leukoc Biol 71:388–400

    CAS  PubMed  Google Scholar 

  • Clevenger AC, Kilbaugh T, Margulies SS (2015) Carotid artery blood flow decreases after rapid head rotation in piglets. J Neurotrauma 32:120–126

    Article  PubMed  PubMed Central  Google Scholar 

  • Cuzzocrea S, Pisano B, Dugo L, Ianaro A, Maffia P, Patel NS, Di Rosa M (2004) Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-γ, reduces acute inflammation. Eur j pharmacol 483(1):79–93

    Article  CAS  PubMed  Google Scholar 

  • Cyrino LA, Cardoso RC, Hackl LP, Nicolau M (2002) Effect of quercetin on plasma extravasation in rat CNS and dura mater by ACE and NEP inhibition. Phytother Res 16:545–549

    Article  CAS  PubMed  Google Scholar 

  • D’Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Rev 36:60–90

    Article  PubMed  Google Scholar 

  • Donkin JJ, Turner RJ, Hassan I, Vink R (2007) Substance P in traumatic brain injury. Prog Brain Res 161:97–109

    Article  CAS  PubMed  Google Scholar 

  • Douglas SD, Leeman SE (2011) Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann N Y Acad Sci 1217:83–95

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  CAS  PubMed  Google Scholar 

  • Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  • Fehlberg S, Gregel CM, Göke A, Göke R (2003) Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO. Br J Pharmacol 139:495–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng J, Fitz Y, Li Y, Fernandez M, Puch IC, Wang D, Solomon SB (2015) Catheterization of the carotid artery and jugular vein to perform hemodynamic measures, infusions and blood sampling in a conscious rat model. J Vis Exp 95. doi:10.3791/5188

  • Gerstein H, Hullinger R, Lindstrom MJ, Burger C (2013) A behavioral paradigm to evaluate hippocampal performance in aged rodents for pharmacological and genetic target validation. PLoS One 8:62360

    Article  Google Scholar 

  • Giorgetti M, Gibbons JA, Bernales S, Alfaro IE, La Rochelle CD, Cremers T, Protter AA (2010) Cognition-enhancing properties of Dimebon in a rat novel object recognition task are unlikely to be associated with acetylcholinesterase inhibition or N-methyl-D-aspartate receptor antagonism. J Pharmacol Exp Ther 333(3):748–757

    Article  CAS  PubMed  Google Scholar 

  • Ghoneim AI, Abdel-Naim AB, Khalifa AE, El-Denshary ES (2002) Protective effects of curcumin against ischaemia/reperfusion insult in rat forebrain. Pharmacol Res 46:273–279

    Article  CAS  PubMed  Google Scholar 

  • Gorelick PB, Scuteri A, Black SE, DeCarli C, Greenberg SM, Iadecola C, Petersen RC (2011) Vascular contributions to cognitive impairment and dementia a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:2672–2713

    Article  PubMed  PubMed Central  Google Scholar 

  • Karasawa JI, Hashimoto K, Chaki S (2008) D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav Brain Res 186(1):78–83

    Article  CAS  PubMed  Google Scholar 

  • Kim AR, Rylett RJ, Shilton BH (2006) Substrate binding and catalytic mechanism of human choline acetyltransferase. Biochemistry 45:14621–14631

    Article  CAS  PubMed  Google Scholar 

  • Korczyn AD, Vakhapova V, Grinberg LT (2012) Vascular dementia. J Neurol Sci 322:2–10

    Article  PubMed  PubMed Central  Google Scholar 

  • Kumar N, Kumar R (2013) Nanotechnology and nanomaterials in the treatment of life-threatening diseases. William Andrew, Norwich, NY

  • Kwon KJ, Kim MK, Lee EJ, Kim JN, Choi BR, Kim SY et al (2014) Effects of donepezil, an acetylcholinesterase inhibitor, on neurogenesis in a rat model of vascular dementia. J Neurol Sci 347:66–77

    Article  CAS  PubMed  Google Scholar 

  • Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47–60

    Article  CAS  PubMed  Google Scholar 

  • Murakami Y, Saito K, Hara A, Zhu Y, Sudo K, Niwa M, Seishima M (2005) Increases in tumor necrosis factor-α following transient global cerebral ischemia do not contribute to neuron death in mouse hippocampus. J Neurochem 93:1616–1622

    Article  CAS  PubMed  Google Scholar 

  • Nandagopal M, Muralidharan P, Thirumurugan G (2010) Behavioral assessment studies in cerebral ischemia induced by bilateral carotid artery occlusion in rats. Ann Biol Res 1:208–223

    Google Scholar 

  • Nimmo AJ, Cernak I, Heath DL, Hu X, Bennett CJ, Vink R (2004) Neurogenic inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats. Neuropeptides 38:40–47

    Article  CAS  PubMed  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  • Pezet S, Cunningham J, Patel J, Grist J, Gavazzi I, Lever IJ, Malcangio M (2002) BDNF modulates sensory neuron synaptic activity by a facilitation of GABA transmission in the dorsal horn. Mol Cell Neurosci 21:51–62

    Article  CAS  PubMed  Google Scholar 

  • Rosso M, Munoz M, Berger M (2012) The role of neurokinin-1 receptor in the microenvironment of inflammation and cancer. Sci World J. doi:10.1100/2012/381434

  • Saxena A, Fedorko JM, Vinayaka CR, Medhekar R, Radić Z, Taylor P, Doctor BP (2003) Aromatic amino-acid residues at the active and peripheral anionic sites control the binding of E2020 (Aricept®) to cholinesterases. Eur J Biochem 270:4447–4458

    Article  CAS  PubMed  Google Scholar 

  • Singh N, Agrawal M, Doré S (2013) Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models. ACS Chem Neurosci 4:1151–1162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stumm RK, Culmsee C, Schäfer MKH, Krieglstein J, Weihe E (2001) Adaptive plasticity in tachykinin and tachykinin receptor expression after focal cerebral ischemia is differentially linked to gabaergic and glutamatergic cerebrocortical circuits and cerebrovenular endothelium. J Neurosci 21:798–811

    CAS  PubMed  Google Scholar 

  • Sun Z, Wang H, Wang J, Zhou L, Yang P (2014) Chemical composition and anti-inflammatory, cytotoxic and antioxidant activities of essential oil from leaves of Mentha piperita grown in China. PLoS One 9:114767

    Article  Google Scholar 

  • Turner RJ, Vink Robert (2013) The role of Substance P in ischaemic brain injury. Brain Sci 3:123–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S (2011) The peroxisome proliferator-activated receptor: a family of nuclear receptors role in various diseases. J Adv Pharm Technol Res 2(4):236–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verma A, Sharma S (2015) Benefecial effect of protein tyrosine phosphatase inhibitor and phytoestrogen in dyslipidemia induced vascular dementia in ovariectomized rats. J Stroke Cerebrovasc Dis. doi:10.1016/j.jstrokecerebrovasdis.2015.02.019

    PubMed  Google Scholar 

  • Vink R, Young A, Bennett CJ, Hu X, Connor CO, Cernak I, Nimmo AJ (2003) Neuropeptide release influences brain edema formation after diffuse traumatic brain injury. Acta Neurochir Suppl 86:257–260

    CAS  PubMed  Google Scholar 

  • Wang L, Guo LL, Wang LH, Zhang GX, Shang J, Murao K, Fu WQ (2015) Oxidative stress and substance P mediate psychological stress-induced autophagy and delay of hair growth in mice. Arch Dermatol Res 307:171–181

    Article  CAS  PubMed  Google Scholar 

  • Wright HM, Clish CB, Mikami T, Hauser S, Yanagi K, Hiramatsu R, Spiegelman BM (2000) A synthetic antagonist for the peroxisome proliferator-activated receptor γ inhibits adipocyte differentiation. J Biol Chem 275:1873–1877

    Article  CAS  PubMed  Google Scholar 

  • Wu WC, Chai CY (2004) Nitric oxide release in the nucleus tractus solitarius during and after bilateral common carotid artery occlusion. Clin Exp Pharmacol Physiol 31:152–158

    Article  CAS  PubMed  Google Scholar 

  • Xiang GQ, Tang SS, Jiang LY, Hong H, Li Q, Wang C, Yin L (2012) PPARγ agonist pioglitazone improves scopolamine-induced memory impairment in mice. J Pharm Pharmacol 6:589–596

    Article  Google Scholar 

  • Zhao Y, Gong CX (2015) From chronic cerebral hypoperfusion to Alzheimer-like brain pathology and neurodegeneration. Cell Mol Neurobiol 35:101–110

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are thankful to Sh. Praveen Garg, Chairman ISF College of Pharmacy, Moga for providing research facilities for this research project.

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Authors and Affiliations

  1. Department of Pharmacology, I.S.F. College of Pharmacy, Moga, Punjab, 142001, India

    Jaspreet Kaur, Shweta Sharma, Manpreet Sandhu & Saurabh Sharma

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  1. Jaspreet Kaur
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  2. Shweta Sharma
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  3. Manpreet Sandhu
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  4. Saurabh Sharma
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Correspondence to Saurabh Sharma.

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Kaur, J., Sharma, S., Sandhu, M. et al. Neurokinin-1 receptor inhibition reverses ischaemic brain injury and dementia in bilateral common carotid artery occluded rats: possible mechanisms. Inflammopharmacol 24, 133–143 (2016). https://doi.org/10.1007/s10787-016-0271-6

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  • DOI: https://doi.org/10.1007/s10787-016-0271-6

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