Traumatic brain injury (TBI) represents a critical public health problem around the world. To date, there are no accurate therapeutic approaches for the management of cardiovascular impairments induce by TBI. In this regard, hydrogen sulfide (H2S), a novel gasotransmitter, has been proposed as a neuro- and cardioprotective molecule. This study was designed to determine the effect of subchronic management with sodium hydrosulfide (NaHS) on hemodynamic, vasopressor sympathetic outflow and sensorimotor alterations produced by TBI. Animals underwent a lateral fluid percussion injury, and changes in hemodynamic variables were measured by pletismographic methods. In addition, vasopressor sympathetic outflow was assessed by a pithed rat model. Last, sensorimotor impairments were evaluated by neuroscore test and beam-walking test. At seven, 14, 21, and 28 days after moderate-severe TBI, the animals showed: (1) a decrease on sensorimotor function in the neuroscore test and beam-walking test; (2) an increase in heart rate, systolic, diastolic, and mean blood pressure; (3) progressive sympathetic hyperactivity; and (4) a decrease in vasopressor responses induced by noradrenaline (α1/2-adrenoceptors agonist) and UK 14,304 (selective α2-adrenoceptor agonist). Interestingly, intraperitoneal daily injections of NaHS, an H2S donor (3.1 and 5.6 mg/kg), during seven days after TBI prevented the development of the impairments in hemodynamic variables, which were similar to those obtained in sham animals. Moreover, NaHS treatment prevented the sympathetic hyperactivity and decreased noradrenaline-induced vasopressor responses. No effects on sensorimotor dysfunction were observed, however. Taken together, our results suggest that H2S ameliorates the hemodynamic and sympathetic system impairments observed after TBI.
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References
1.
GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. (2019). Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18, 56–87.
2.
FriedenT.R., HouryD., and BaldwinG. (2015). Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. CDC NIH Rep. to CongrESS, 1–74.
3.
KaurP., and SharmaS. (2018). Recent advances in pathophysiology of traumatic brain injury. Curr. Neuropharmacol. 16, 1224–1238.
4.
D'AmbrosioR., FairbanksJ.P., FenderJ.S., BornD.E., DoyleD.L., and MillerJ.W. (2004). Post-traumatic epilepsy following fluid percussion injury in the rat. Brain, 127, 304–314.
5.
LozanoD., Gonzales-PortilloG.S., AcostaS., de la PenaI., TajiriN., KanekoY., and BorlonganC.V. (2015). Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr. Dis. Treat. 11, 97–106.
6.
JiangX., HuangY., LinW., GaoD., and FeiZ. (2013). Protective effects of hydrogen sulfide in a rat model of traumatic brain injury via activation of mitochondrial adenosine triphosphate-sensitive potassium channels and reduction of oxidative stress. J. Surg. Res. 184, e27–e35.
7.
McIntoshT.K., VinkR., NobleL., YamakamiI., FernyakS., SoaresH., and FadenA.L. (1989). Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model. Neuroscience, 28, 233–244.
8.
GoldsteinB., ToweillD., LaiS., SonnenthalK., and KimberlyB. (1998). Uncoupling of the autonomic and cardiovascular systems in acute brain injury. Am. J. Physiol. 275, R1287–R1292.
9.
McMahonC.G., KennyR., BennettK., LittleR., and KirkmanE. (2011). Effect of acute traumatic brain injury on baroreflex function. Shock, 35, 53–58.
10.
HilzM.J., WangR., MarkusJ., AmmonF., HöslK.M., FlanaganS.R., WinderK., and KoehnJ. (2017). Severity of traumatic brain injury correlates with long-term cardiovascular autonomic dysfunction. J. Neurol. 264, 1956–1967.
11.
HeffernanD.S., InabaK., ArbabiS., and CottonB.A. (2010). Sympathetic hyperactivity after traumatic brain injury and the role of beta-blocker therapy. J. Trauma, 69, 1602–1609.
12.
ChenJ., ChenW., HanK., QiE., ChenR., YuM., HouL., and LvL. (2019). Effect of oxidative stress in rostral ventrolateral medulla on sympathetic hyperactivity after traumatic brain injury. Eur. J. Neurosci. 50, 1972–1980.
13.
LvL.Q., HouL.J., YuM.K., QiX.Q., ChenH.R., ChenJ.X., HuG.H., LuoC., and LuY.C. (2010). Prognostic influence and magnetic resonance imaging findings in paroxysmal sympathetic hyperactivity after severe traumatic brain injury. J. Neurotrauma, 27, 1945–1950.
14.
MengG., ZhaoS., XieL., HanY., and JiY. (2018). Protein S-sulfhydration by hydrogen sulfide in cardiovascular system. Br. J. Pharmacol. 175, 1146–1156.
15.
PanthiS., ManandharS., and GautamK. (2018). Hydrogen sulfide, nitric oxide, and neurodegenerative disorders. Transl. Neurodegener. 7, 3.
16.
CenturiónD., de la CruzS.H., Castillo-SantiagoS.V, Becerril-ChacónM.E., Torres-PérezJ.A., and Sánchez-LópezA. (2018). NaHS prejunctionally inhibits the cardioaccelerator sympathetic outflow in pithed rats. Eur. J. Pharmacol. 823, 35–40.
17.
CenturiónD., de la CruzS.H., Gutiérrez-LaraE.J., Beltrán-OrnelasJ.H., and Sánchez-LópezA. (2016). Pharmacological evidence that NaHS inhibits the vasopressor responses induced by stimulation of the preganglionic sympathetic outflow in pithed rats. Eur. J. Pharmacol. 770, 40–45.
18.
GuoQ., WuY., XueH., XiaoL., JinS., and WangR. (2016). Perfusion of isolated carotid sinus with hydrogen sulfide attenuated the renal sympathetic nerve activity in anesthetized male rats. Physiol. Res. 65, 413–423.
19.
CheX., FangY., SiX., WangJ., HuX., ReisC., and ChenS. (2018). The role of gaseous molecules in traumatic brain injury: an updated review. Front. Neurosci. 12, 392.
20.
ZhangJ.Y., DingY.P., WangZ., KongY., GaoR., and ChenG. (2017). Hydrogen sulfide therapy in brain diseases: from bench to bedside. Med. Gas Res. 7, 113–119.
21.
ZhangM., ShanH., WangT., LiuW., WangY., WangL., ZhangL., ChangP., DongW., ChenX., and TaoL. (2013). Dynamic change of hydrogen sulfide after traumatic brain injury and its effect in mice. Neurochem. Res. 38, 714–725.
22.
ZhangM., ShanH., ChangP., MaL., ChuY., ShenX., WuQ., WangZ., LuoC., WangT., ChenX., and TaoL. (2017). Upregulation of 3-MST relates to neuronal autophagy after traumatic brain injury in mice. Cell. Mol. Neurobiol. 37, 291–302.
23.
CampoloM., EspositoE., AhmadA., Di PaolaR., PaternitiI., CordaroM., BruschettaG., WallaceJ.L., and CuzzocreaS. (2014). Hydrogen sulfide-releasing cyclooxygenase inhibitor ATB-346 enhances motor function and reduces cortical lesion volume following traumatic brain injury in mice. J. Neuroinflammation, 11, 196.
24.
KarimiS.A., HosseinmardiN., JanahmadiM., SayyahM., and HajisoltaniR. (2017). The protective effect of hydrogen sulfide (H2S) on traumatic brain injury (TBI) induced memory deficits in rats. Brain Res. Bull. 134, 177–182.
25.
ZhangM., ShanH., ChangP., WangT., DongW., ChenX., and TaoL. (2014). Hydrogen sulfide offers neuroprotection on traumatic brain injury in parallel with reduced apoptosis and autophagy in mice. PLoS One, 9, e87241.
26.
XuK., WuF., XuK., LiZ., WeiX., LuQ., JiangT., WuF., XuX., XiaoJ., ChenD., and ZhangH. (2018). NaHS restores mitochondrial function and inhibits autophagy by activating the PI3K/Akt/mTOR signalling pathway to improve functional recovery after traumatic brain injury. Chem. Biol. Interact. 286, 96–105.
27.
National Reseach Council of the National Academies. (2011). Guide for the Care and Use of Laboratory Animals, 8th ed. Washington, DC: The National Academies Press.
28.
GomezC.B., de la CruzS.H., Medina-TerolG.J., Beltran-OrnelasJ.H., Sánchez-LópezA., Silva-VelascoD.L., and CenturiónD. (2019). Chronic administration of NaHS and L-Cysteine restores cardiovascular changes induced by high-fat diet in rats. Eur. J. Pharmacol. 863, 172707.
29.
HausserN., JohnsonK., ParsleyM.A., GuptarakJ., SprattH., and SellS.L. (2018). Detecting behavioral deficits in rats after traumatic brain injury. J. Vis. Exp. 2018, 56044.
30.
OhlssonA.L., and JohanssonB.B. (1995). Environment influences functional outcome of cerebral infarction in rats. Stroke, 26, 644–649.
31.
KleinmanL.I., and RadfordE.P. (1964). Ventilation standards for small mammals. J. Appl. Physiol. 19, 360–362.
32.
CenturiónD., Cobos-PucL.E., Ramírez-RosasM.B., Gómez-DíazB., Sánchez-LópezA., and VillalónC.M. (2009). Pithed rat model for searching vasoactive drugs and studying the modulation of the sympathetic and non- adrenergic non-cholinergic outflow. In: Rocha, L., and Granados-Soto, V. (eds). Models in Neuropharmacology. Kerala, India: Transworld Research Network., pps. 91–97.
33.
GillespieJ.S., and MuirT.C. (1967). A method of stimulating the complete sympathetic outflow from the spinal cord to blood vessels in the pithed rat. Br. J. Pharmacol. Chemother. 30, 78–87.
34.
Ruiz-SalinasI., RochaL., Marichal-CancinoB.A., and VillalónC.M. (2016). Cardiovascular alterations during the interictal period in awake and pithed amygdala-kindled rats. Basic Clin. Pharmacol. Toxicol. 119, 165–172.
35.
McIntoshT.K., HeadV.A., and FadenA.I. (1987). Alterations in regional concentrations of endogenous opioids following traumatic brain injury in the cat. Brain Res. 425, 225–233.
36.
FadenA.I., DemediukP., PanterS.S., and VinkR. (1989). The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science, 244, 798–800.
37.
WangX., GaoX., MichalskiS., ZhaoS., and ChenJ. (2016). Traumatic brain injury severity affects neurogenesis in adult mouse hippocampus. J. Neurotrauma, 33, 721–733.
38.
AnC., JiangX., PuH., HongD., ZhangW., HuX., and GaoY. (2016). Severity-dependent long-term spatial learning-memory impairment in a mouse model of traumatic brain injury. Transl. Stroke Res. 7, 512–520.
39.
Ndode-EkaneX.E., Santana-GomezC., Casillas-EspinosaP.M., AliI., BradyR.D., SmithG., AndradeP., ImmonenR., PuhakkaN., HudsonM.R., BraineE.L., ShultzS.R., StabaR.J., O'BrienT.J., and PitkanenA. (2019). Harmonization of lateral fluid-percussion injury model production and post-injury monitoring in a preclinical multicenter biomarker discovery study on post-traumatic epileptogenesis. Epilepsy Res. 151, 7–16.
40.
O'BryantA.J., AllredR.P., MaldonadoM.A., CormackL.K., and JonesT.A. (2011). Breeder and batch-dependent variability in the acquisition and performance of a motor skill in adult Long-Evans rats. Boehav. Brain Res. 224, 112–120.
41.
KrishnamoorthyV., Rowhani-RahbarA., ChaikittisilpaN., GibbonsE.F., RivaraF.P., TemkinN.R., QuistbergA., and VavilalaM.S. (2017). Association of early hemodynamic profile and the development of systolic dysfunction following traumatic brain injury. Neurocrit. Care, 26, 379–387.
42.
KimuraH. (2012). Physiological and pathophysiological functions of hydrogen sulfide. In: Hermann, A., Sitdikova, G.F., and Weiger, T.M. (eds). Gasotransmitters: Physiology and Pathophysiology. Berlin: Springer, pps. 71–98.
43.
SobloskyJ.S., MatthewsM.A., DavidsonJ.F., TaborS.L., and CareyM.E. (1996). Traumatic brain injury of the forelimb and hindlimb sensorimotor areas in the rat: physiological, histological and behavioral correlates. Behav. Brain Res. 79, 79–92.
44.
SellS.L., JohnsonK., DewittD.S., and ProughD.S. (2017). Persistent behavioral deficits in rats after parasagittal fluid percussion injury. J. Neurotrauma, 34, 1086–1096.
45.
HammondF.M., CorriganJ.D., KetchumJ.M., MalecJ.F., Dams-O'ConnorK., HartT., NovackT.A., BognerJ., DahdahM.N., and WhiteneckG.G. (2019). Prevalence of medical and psychiatric comorbidities following traumatic brain injury. J. Head Trauma Rehabil. 34, E1–E10.
46.
Eric NyamT.T., HoC.H., ChioC.C., LimS.W., WangJ.J., ChangC.H., KuoJ.R., and WangC.C. (2019). Traumatic brain injury increases the risk of major adverse cardiovascular and cerebrovascular events: a 13-year, population-based study. World Neurosurg. 122, e740–e753.
47.
LarsonB.E., StockwellD.W., BoasS., AndrewsT., WellmanG.C., LocketteW., and FreemanK. (2012). Cardiac reactive oxygen species after traumatic brain injury. J. Surg. Res, 173, e73–e81.
48.
UmemotoY., PatelA., HuynhT., and ChitravanshiV.C. (2019). Wogonin attenuates the deleterious effects of traumatic brain injury in anesthetized Wistar rats. Eur. J. Pharmacol. 848, 121–130.
49.
YangG., WuL., JiangB., YangW., QiJ., CaoK., MengQ., MustafaA.K., MuW., ZhangS., SnyderS.H., and WangR. (2008). H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science, 322, 587–590.
50.
ZhongG.Z., ChenF.R., ChengY.Q., TangC.S., and DuJ.B. (2003). The role of hydrogen sulfide generation in the pathogenesis of hypertension in rats induced by inhibition of nitric oxide synthase. J. Hypertens. 21, 1879–1885.
51.
HuangP., ChenS., WangY., LiuJ., YaoQ., HuangY., LiH., ZhuM., WangS., LiL., TangC., TaoY., YangG., DuJ., and JinH. (2015). Down-regulated CBS/H2S pathway is involved in high-salt-induced hypertension in Dahl rats. Nitric Oxide, 46, 192–203.
52.
GoodwinL.R., FrancomD., DiekenF.P., TaylorJ.D., WarenyciaM.W., ReiffensteinR.J., and DowlingG. (1989). Determination of sulfide in brain tissue by gas dialysis/ion chromatography: postmortem studies and two case reports. J. Anal. Toxicol. 13, 105–109.
53.
KhademullahC.S., and FergusonA. V. (2013). Depolarizing actions of hydrogen sulfide on hypothalamic paraventricular nucleus neurons. PLoS One, 8, e64495.
54.
MalikR., and FergusonA. V. (2016). Hydrogen sulfide depolarizes neurons in the nucleus of the solitary tract of the rat. Brain Res. 1633, 1–9.
55.
DuanX.C., LiuS.Y., GuoR., XiaoL., XueH.M., GuoQ., JinS., and WuY.M. (2015). Cystathionine-β-synthase gene transfer into rostral ventrolateral medulla exacerbates hypertension via nitric oxide in spontaneously hypertensive rats. Am. J. Hypertens. 28, 1106–1113.
56.
GengB., YangJ., QiY., ZhaoJ., PangY., DuJ., and TangC. (2004). H2S generated by heart in rat and its effects on cardiac function. Biochem. Biophys. Res. Commun. 313, 362–368.
57.
HosokiR., MatsukiN., and KimuraH. (1997). The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem. Biophys. Res. Commun. 237, 527–31.
58.
McCorryL.K. (2007). Physiology of the autonomic nervous system. Am. J. Pharm. Educ. 71, 78.
59.
BishopS., DechR., BakerT., ButzM., AravinthanK., and NearyJ.P. (2017). Parasympathetic baroreflexes and heart rate variability during acute stage of sport concussion recovery. Brain Inj. 31, 247–259.
60.
BaguleyI.J., HeriseanuR.E., FelminghamK.L., and CameronI.D. (2006). Dysautonomia and heart rate variability following severe traumatic brain injury. Brain Inj. 20, 437–444.
61.
Fernandez-OrtegaJ.F., BaguleyI.J., GatesT.A., Garcia-CaballeroM., Quesada-GarciaJ.G., and Prieto-PalominoM.A. (2017). Catecholamines and paroxysmal sympathetic hyperactivity after traumatic brain injury. J. Neurotrauma, 34, 109–114.
62.
RosnerM.J., NewsomeH.H., and BeckerD.P. (1984). Mechanical brain injury: the sympathoadrenal response. J. Neurosurg. 61, 76–86.
63.
TümerN., SvetlovS., WhiddenM., KirichenkoN., PrimaV., ErdosB., ShermanA., KobeissyF., YezierskiR., ScarpaceP.J., VierckC., and WangK.K.W. (2013). Overpressure blast-wave induced brain injury elevates oxidative stress in the hypothalamus and catecholamine biosynthesis in the rat adrenal medulla. Neurosci. Lett. 544, 62–67.
64.
KoboriN., HuB., and DashP.K. (2011). Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction. Neuroscience, 172, 293–302.
65.
LevinB.E., PanS., and Dunn-MeynellA. (1994). Chronic alterations in rat brain α-adrenoceptors following traumatic brain injury. Restor. Neurol. Neurosci. 7, 5–12.
66.
GoddeauR.P., SilvermanS.B., and SimsJ.R. (2007). Dexmedetomidine for the treatment of paroxysmal autonomic instability with dystonia. Neurocrit. Care, 7, 217–220.
67.
WuJ., VogelT., GaoX., LinB., KulwinC., and ChenJ. (2018). Neuroprotective effect of dexmedetomidine in a murine model of traumatic brain injury. Sci. Rep. 8, 4935.
68.
NissinenJ., AndradeP., NatunenT., HiltunenM., MalmT., KanninenK., SoaresJ.I., ShatilloO., SallinenJ., Ndode-EkaneX.E., and PitkänenA. (2017). Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy. Epilepsy Res. 136, 18–34.
69.
Dominguez-RodriguezM., DrobnyH., BoehmS., and SalzerI. (2017). Electrophysiological investigation of the subcellular fine tuning of sympathetic neurons by hydrogen sulfide. Front. Pharmacol. 8, 522.
70.
ZiolkowskiN., and GroverA.K. (2010). Functional linkage as a direction for studies in oxidative stress: alpha-adrenergic receptors. Can. J. Physiol. Pharmacol. 88, 220–232.
71.
SunG.C., HoW.Y., ChenB.R., ChengP.W., ChengW.H., HsuM.C., YehT.C., HsiaoM., LuP.J., and TsengC.J. (2015). GPCR dimerization in brainstem nuclei contributes to the development of hypertension. Br. J. Pharmacol. 172, 2507–2518.
72.
Borroto-EscuelaD.O., CarlssonJ., AmbroginiP., NarváezM., WydraK., TarakanovA.O., LiX., MillónC., FerraroL., CuppiniR., TanganelliS., LiuF., FilipM., Diaz-CabialeZ., and FuxeK. (2017). Understanding the role of GPCR heteroreceptor complexes in modulating the brain networks in health and disease. Front. Cell. Neurosci. 11, 37.
73.
GuoQ., JinS., WangX.L., WangR., XiaoL., HeR.R., and WuY.M. (2011). Hydrogen sulfide in the rostral ventrolateral medulla inhibits sympathetic vasomotor tone through ATP-sensitive K+ channels. J. Pharmacol. Exp. Ther. 338, 458–465.
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