Paroxysmal sympathetic hyperactivity (PSH) is a common clinical feature secondary to ischemic stroke (IS) due to the loss of sympathetic nervous system (SNS) inhibition without parasympathetic involvement [1]. The paraventricular nucleus (PVN) of the hypothalamus controls the sympathetic tone and hypothalamic injury can be accompanied by sympathetic overactivity [2]. Hydrogen sulfide (H2S) is an endogenous gaseous signaling molecule with a neuroprotective function. It was found that Inhalation of H2S attenuates IS-induced injury in rats via inhibition of oxidative stress, inflammation, apoptosis, and regulation of cerebral blood flow [3].
In the present study, Sun et al. [4] hypothesized that H2S could ameliorate the PSH induced by IS in both humans and rats, and its alteration was involved in the pathogenesis of PSH.
They investigated IS patients who were divided into malignant (MCI) and non-malignant cerebral infarction (NMCI) groups and the authors found that PSH was associated with the severity of IS and more plasma norepinephrine (NE) was positively correlated with levels of creatine kinase, glutamate transaminase, and creatinine respectively. The 1-year survival rate of patients with high plasma NE levels was lower. Moreover, the cerebrospinal fluid H2S levels were negatively associated with PSH. The plasma NE level as a predictor for neurological outcomes and survival in IS patients is controversial. Some studies have supposed that plasma NE does not predict the neurological outcome at one month in IS patients [5]. However, others proved that plasma NE predicts autonomic dysfunction and risk of death in IS patients [6, 7].
In the present study, IS in rats was induced by the right middle cerebral artery occlusion (MCAO). H2S donor (NaHS) or inhibitor (aminooxy-acetic acid, AOAA) were microinjected into the hypothalamic paraventricular nucleus (PVN). The authors found that the hypothalamus of rats with MCAO showed increased activity, especially in the PVN region. The levels of H2S in PVN of the rats with MCAO were reduced, while the blood pressure and renal sympathetic discharge were increased, that ameliorated by NaHS and exacerbated by AOAA. These findings are supported by Coletti et al. who fund that hypothalamic H2S is involved in the hypothalamic control of blood pressure, HR, and temperature [8].
The present study shows that NaHS completely reduced the disulfide bond of NMDAR1 in PC12 cells. The inhibition of NMDAR by MK-801 microinjected in PVN of rats with MCAO lowered blood pressure and renal sympathetic discharge. The neuroprotective effect of NMDAR signaling inhibitors is previously demonstrated in various IS animals [9] and the antioxidant effect of H2S was reported as it cleaves the disulfide bond of VEGFR2 [10], TGF-β1 [11], CD36 [12], and PX-12 [13].
The current study could conclude that PSH may be associated with disease progression and survival in patients with IS. Abnormal activity, NMDAR signaling, and the H2S level of PVN were involved in regulating sympathetic activity after cerebral infarction. Modulating the hypothalamic active state or H2S release/supplementation may be beneficial in treating PSH. These findings might provide a new strategy for the prevention and treatment of IS-induced PSH patients.
References
Perkes IE, Menon DK, Nott MT, Baguley IJ. Paroxysmal sympathetic hyperactivity after acquired brain injury: a review of diagnostic criteria. Brain INJ. 2011;25:925–32.
Lee SJ, Jang SH. Hypothalamic injury in spontaneous subarachnoid hemorrhage: a diffusion tensor imaging study. Clin Auton Res. 2021;31:321–2.
Ding JS, Zhang Y, Wang TY, Li X, Ma C, Xu ZM, et al. Therapeutic applications of hydrogen sulfide and novel donors for cerebral ischemic stroke: a narrative review. Med Gas Res. 2023;13:7–9.
Sun J, Miao Y, Wang P, Guo Q, Tian D, Xue H, et al. Decreased levels of hydrogen sulfide in the hypothalamic paraventricular nucleus contribute to sympathetic hyperactivity induced by cerebral infarction. Hypertens Res. 2024;47:1323–37.
Oto J, Suzue A, Inui D, Fukuta Y, Hosotsubo K, Torii M, et al. Plasma proinflammatory and anti-inflammatory cytokine and catecholamine concentrations as predictors of neurological outcome in acute stroke patients. J Anesth. 2008;22:207–12.
Chamorro A, Amaro S, Vargas M, Obach V, Cervera A, Gomez-Choco M, et al. Catecholamines, infection, and death in acute ischemic stroke. J Neurol Sci. 2007;252:29–35.
Strittmatter M, Meyer S, Fischer C, Georg T, Schmitz B. Location-dependent patterns in cardio-autonomic dysfunction in ischaemic stroke. Eur Neurol. 2003;50:30–8.
Coletti R, Almeida-Pereira G, Elias LL, Antunes-Rodrigues J. Effects of hydrogen sulfide 562 (H2S) on water intake and vasopressin and oxytocin secretion induced by fluid deprivation. 563. Horm Behav. 2015;67:12–20.
Liu CW, Liao KH, Tseng H, Wu CM, Chen HY, Lai TW. Hypothermia but not NMDA 571 receptor antagonism protects against stroke induced by distal middle cerebral arterial occlusion 572 in mice. PLoS One. 2020;15:e0229499.
Tao BB, Liu SY, Zhang CC, Fu W, Cai WJ, Wang Y, et al. VEGFR2 functions as an H2S-targeting receptor protein kinase with its novel Cys1045-Cys1024 disulfide bond serving as a specific molecular switch for hydrogen sulfide actions in vascular endothelial cells. Antioxid Redox Signal. 2013;19:448–64.
Huang Y, Zhang Z, Huang Y, Mao Z, Yang X, Nakamura Y, et al. Induction of inactive TGF-beta1 monomer formation by hydrogen sulfide contributes to its suppressive effects on Ang II- and TGF-beta1-induced EMT in renal tubular epithelial cells. Biochem Biophys Res Commun. 2018;501:534–40.
Wang R, Tao B, Fan Q, Wang S, Chen L, Zhang J, et al. Fatty-acid receptor CD36 functions as a hydrogen sulfide-targeted receptor with its Cys333-Cys272 disulfide bond serving as a specific molecular switch to accelerate gastric cancer metastasis. EBioMedicine 2019;45:108–23.
Mao Z, Yang X, Mizutani S, Huang Y, Zhang Z, Shinmori H, et al. Hydrogen sulfide mediates tumor cell resistance to thioredoxin inhibitor. Front Oncol. 2020;10:252.
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Mahmoud, R.S.G. Involvement of hydrogen sulfide in the pathogenesis of ischemic stroke-induced paroxysmal sympathetic hyperactivity. Hypertens Res (2024). https://doi.org/10.1038/s41440-024-01691-x
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DOI: https://doi.org/10.1038/s41440-024-01691-x