Neuroprotective Roles of l-Cysteine in Attenuating Early Brain Injury and Improving Synaptic Density via the CBS/H2S Pathway Following Subarachnoid Hemorrhage in Rats

Abstract

l-Cysteine is a semi-essential amino acid and substrate for cystathionine-β-synthase (CBS) in the central nervous system. We previously reported that NaHS, an H2S donor, significantly alleviated brain damage after subarachnoid hemorrhage (SAH) in rats. However, the potential therapeutic value of l-cysteine and the molecular mechanism supporting these beneficial effects have not been determined. This study was designed to investigate whether l-cysteine could attenuate early brain injury following SAH and improve synaptic function by releasing endogenous H2S. Male Wistar rats were subjected to SAH induced by cisterna magna blood injection, and l-cysteine was intracerebroventricularly administered 30 min after SAH induction. Treatment with l-cysteine stimulated CBS activity in the prefrontal cortex (PFC) and H2S production. Moreover, l-cysteine treatment significantly ameliorated brain edema, improved neurobehavioral function, and attenuated neuronal cell death in the PFC; these effects were associated with a decrease in the Bax/Bcl-2 ratio and the suppression of caspase-3 activation 48 h after SAH. Furthermore, l-cysteine treatment activated the CREB–brain-derived neurotrophic factor (BDNF) pathway and intensified synaptic density by regulating synapse proteins 48 h after SAH. Importantly, all the beneficial effects of l-cysteine in SAH were abrogated by amino-oxyacetic acid, a CBS inhibitor. Based on these findings, l-cysteine may play a neuroprotective role in SAH by inhibiting cell apoptosis, upregulating CREB–BDNF expression, and promoting synaptic structure via the CBS/H2S pathway.

Cryptotanshinone Attenuates Oxygen-Glucose Deprivation/ Recovery-Induced Injury in an in vitro Model of Neurovascular Unit

“…The Bcl-2 family member Bax was markedly up-regulated after OGD/R, which resulted in the release of cytochrome c to the cytosol. Bcl-2 exerts the anti-apoptosis efficiency through inhibiting the function of Bax (30, 31). We found that the OGD/R-induced up-regulation of Bax/Bcl-2 ratio could be reversed by CTs pre-treatment.…”

“…Moreover, we analyzed the activation of Caspase-3 and the degradation of PARP. Cytochrome c release triggers the cleavage of Caspase-3 to activate the Caspase-3 protein, which results in DNA fragmentation and cell apoptosis by cleaving PARP (31, 32). Our data revealed that pre-treatment with CTs prevented the OGD/R-induced increase in cleaved-Caspase-3 and cleaved-PARP.…”

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…In several animal model studies, Hcy brought about synaptic dysfunction, oxidative stress, neurochemical imbalance, and apoptosis, resulting in cognitive impairment and neuronal cell death. Thus, an Hcy-induced neurotoxicity model might be suitable for the study of AD ( Ataie et al, 2010a , b , c ; Wei et al, 2014 ; Kamat et al, 2016 ; Li T. et al, 2017 ). Hcy has been shown to modulate glutamate receptors, which leads to various neurotoxic effects.…”

Inhibition of Necroptosis Rescues SAH-Induced Synaptic Impairments in Hippocampus via CREB-BDNF Pathway

“…It has been reported that BDNF and CREB are closely involved in the impairment seen with brain injury after SAH (Li et al, 2017a,b). BDNF is a neuroprotective protein involved in synaptic plasticity and is known to be the basis of memory processes (Seoane et al, 2011).…”

“…An experimental SAH model was made using a double blood injection model according to our previous study (Hu et al, 2016; Li et al, 2017b). Briefly, 3.5% isoflurane was used to induce anesthesia and 2.5% to maintain it.…”