Oxytocin Improves Intracerebral Hemorrhage Outcomes by Suppressing Neuronal Pyroptosis and Mitochondrial Fission

Abstract

Background: Intracerebral hemorrhage (ICH) causes severe sensorimotor dysfunction and cognitive decline which are aggravated by secondary brain injury, yet there are no effective management to alleviate these outcomes. Pyroptosis is strongly related to neuroinflammation, which plays a crucial role in the pathophysiological processes of secondary brain injury after ICH. OXT (oxytocin), as a pleiotropic neuropeptide, has multiple functions including anti-inflammation and antioxidation. This study aims to investigate the role of OXT in improving ICH outcomes and the underlying mechanisms. Methods: C57BL/6 mice were used to establish the ICH model by autologous blood injection. OXT was administered intranasally (0.2 μg/g) after ICH. Combing behavioral tests, Western blot, immunofluorescence staining, electron microscopy, and pharmacological approaches, we evaluated the effect of intranasal OXT application on neurological outcomes after ICH and explored the underlying mechanism. Results: Endogenous OXT level was decreased, whereas OXTR (oxytocin receptor) expression was increased after ICH. OXT treatment improved the short-term and long-term neurological functions and alleviated neuronal pyroptosis and neuroinflammation. In addition, OXT reduced excessive mitochondrial fission and mitochondrial-derived oxidative stress 3 days after ICH. OXT decreased the expression of pyroptotic and proinflammatory factors including NLRP3 (NOD-like receptor protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), GSDMD (gasdermin D), caspase-1, IL (interleukin)-1β, and IL-18 and increased the expression of p-PKA (phospho-protein kinase A) and p-DRP1 (S637; DRP1 [dynamin-related protein 1] phosphorylation at Ser637). OXT-induced neuroprotective effects were blocked by either OXTR inhibitor or PKA inhibitor. Conclusions: Intranasal application of OXT can ameliorate neurological deficits and alleviate neural pyroptosis, inflammation, and excessive mitochondrial fission via OXTR/p-PKA/DRP1 signaling pathway after ICH. Thus, OXT administration may be a potential therapeutic strategy to improve the prognosis of ICH.

Angiostrongylus cantonensis induces energy imbalance and dyskinesia in mice by reducing the expression of melanin-concentrating hormone

“…In noninfectious central nervous system diseases such as intracerebral hemorrhage (ICH), PD, AD, and narcolepsy, hormones demonstrate differential expression and regulatory impacts. In ICH mouse models, there is a decrease in endogenous OXT levels and an increase in oxytocin receptor (OXTR) expression [ 34 ]. Melatonin, neural stem cell transplantation, or their combination have shown improvement in rotational behavior in PD mouse models [ 35 ].…”

“…In the ventromedial hypothalamic nucleus (VMH), increased OXT induces satiety in rats, significantly enhancing energy expenditure and physical activity [ 42 ]. Intranasal OXT administration can mitigate sensory–motor dysfunction and cognitive decline due to ICH, reducing inflammation via the OXTR/p-PKA/DRP1 signaling pathway [ 34 ]. FSH impacts fat reduction, thermogenesis, and serum cholesterol, and influences Alzheimer's disease-like phenotypes through the neuron C/EBPβ–δ-secretase pathway [ 36 ].…”

Mitochondrial stress: a key role of neuroinflammation in stroke

“…For example, excessive mitochondrial fission was observed in ICH [ 11 ]. Suppression of excessive mitochondrial fission seems to contribute to reduce NLRP3 and pro-inflammatory including IL-1β, IL-18, consequently, attenuate neuronal pyroptosis in ICH [ 152 ]. MtROS and mtDNA have been found to play the key role in the activation of NLRP3 inflammasomes.…”

Pharmacological intervention of curcumin via the NLRP3 inflammasome in ischemic stroke

“…The suppression of ER stress and/or ROS generation has also been shown to alleviate NLRP3-mediated inflammation in stroke cases by inhibiting Drp1-related mitochondrial function ( Guo et al, 2018 ). Moreover, oxytocin reduces mitochondrial fission and oxidative stress within 3 days of intracerebral hemorrhage by downregulating NLRP3, ASC, and caspase-1 expressions and upregulating p-PKA and p-DRP1 expressions to alleviate neurological dysfunction ( Yang et al, 2023b ). These were revised by oxytocin or PKA inhibitors ( Yang et al, 2023b ), indicating that mitochondrial fission is related to the activation of NLRP3 inflammasome.…”