Inhibition of Inducible Nitric Oxide Synthase Attenuates Deficits in Synaptic Plasticity and Brain Functions Following Traumatic Brain Injury
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Traumatic brain injury (TBI), resulting from external force on the head, usually leads to long-term deficits in motor and cognitive functions. Inducible nitric oxide synthase (iNOS)-mediated excessive inflammation could exacerbate brain damage after TBI. The present study therefore investigated the potential neuroprotective effects of iNOS inhibition after TBI. Male C57BL/6J mice were subjected to controlled cortical impact injury and then treated with high selective iNOS inhibitor 1400W. Expression of iNOS mRNA was determined by quantitative RT-PCR. Western blotting was carried out to determine iNOS protein levels. Motor and cognitive functions, and long-term potentiation (LTP) in the medial prefrontal cortex (mPFC) and hippocampus were examined. Expression of iNOS was induced after TBI in a temporal manner. Treatment with 1400W after TBI improved motor and cognitive functions. TBI mice showed deficits in LTP in both the mPFC and hippocampus, and treatment with 1400W could rescue this impairment. Inhibition of iNOS attenuated deficits in synaptic plasticity and brain functions after TBI. The neuroprotective effect of iNOS inhibition on cognitive function might be via rescuing the TBI-induced LTP impairment.
KeywordsTraumatic brain injury (TBI) Neuroprotection Inhibitor Inducible nitric oxide synthase (iNOS) Behaviors
Compliance with Ethical Standards
Research Involving Human Participants and/or Animals
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Conflict of Interest
The authors declare that they have no conflict of interest.
- 9.Schinzel R and Tegtmeier F. Chapter 8—nitric oxide synthase inhibitors in traumatic brain injury A2—Heidenreich, Kim A. New therapeutics for traumatic brain injury. San Diego, Academic Press; 2017. pp. 133–144.Google Scholar
- 10.Iadecola C, Zhang F, Xu X. Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Phys. 1995;268:R286–92.Google Scholar
- 12.Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1997;17:9157–64.Google Scholar
- 13.Stover JF, Belli A, Boret H, Bulters D, Sahuquillo J, Schmutzhard E, et al. Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized phase IIa trial (NOSTRA). J Neurotrauma. 2014;31:1599–606. https://doi.org/10.1089/neu.2014.3344.CrossRefPubMedGoogle Scholar
- 17.Shono Y, Tuckett AZ, Liou HC, Doubrovina E, Derenzini E, Ouk S, et al. Characterization of a c-Rel inhibitor that mediates anticancer properties in hematologic malignancies by blocking NF-kappaB-controlled oxidative stress responses. Cancer Res. 2016;76:377–89. https://doi.org/10.1158/0008-5472.can-14-2814.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Jafarian-Tehrani M, Louin G, Royo NC, Besson VC, Bohme GA, Plotkine M, et al. 1400W, a potent selective inducible NOS inhibitor, improves histopathological outcome following traumatic brain injury in rats. Nitric Oxide. 2005;12:61–9. https://doi.org/10.1016/j.niox.2004.12.001.CrossRefPubMedGoogle Scholar
- 20.Laskowitz DT, Wang H, Chen T, Lubkin DT, Cantillana V, Tu TM, et al. Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model. Sci Rep. 2017;7:46461. https://doi.org/10.1038/srep46461.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Wang ZM, Qi YJ, Wu PY, Zhu Y, Dong YL, Cheng ZX, et al. Neuroactive steroid pregnenolone sulphate inhibits long-term potentiation via activation of alpha2-adrenoreceptors at excitatory synapses in rat medial prefrontal cortex. Int J Neuropsychopharmacol. 2008;11:611–24. https://doi.org/10.1017/s1461145707008334.PubMedGoogle Scholar
- 25.Petrov T, Page AB, Owen CR, Rafols JA. Expression of the inducible nitric oxide synthase in distinct cellular types after traumatic brain injury: an in situ hybridization and immunocytochemical study. Acta Neuropathol. 2000;100:196–204. https://doi.org/10.1007/s004019900167.CrossRefPubMedGoogle Scholar
- 28.Katsumoto S, Smith SME, Martasek P, Salerno JC. Competition and binding of arginine, imidazole, and aminoguanidine to endothelial nitric oxide synthase: aminoguanidine is a poor model for substrate, intermediate, and arginine analog inhibitor binding. Nitric Oxide. 2003;8:149–54. https://doi.org/10.1016/S1089-8603(02)00118-0.CrossRefPubMedGoogle Scholar
- 33.Louin G, Marchand-Verrecchia C, Palmier B, Plotkine M, Jafarian-Tehrani M. Selective inhibition of inducible nitric oxide synthase reduces neurological deficit but not cerebral edema following traumatic brain injury. Neuropharmacology. 2006;50:182–90. https://doi.org/10.1016/j.neuropharm.2005.08.020.CrossRefPubMedGoogle Scholar
- 35.Togashi H, Ueno K-I, Mori K, Matsumoto M, Itoh Y, Shinohara K, et al. Nitric oxide production and long-term potentiation in the rat hippocampus following transient cerebral ischemia. In: Kitabatake A, Sakuma I, editors. Recent advances in nitric oxide research. Tokyo: Springer; 1999. p. 53–65.CrossRefGoogle Scholar