Therapeutic effects of L-Cysteine in newborn mice subjected to hypoxia-ischemia brain injury via the CBS/H2S system: Role of oxidative stress and endoplasmic reticulum stress

Abstract

Neonatal hypoxic-ischemic (HI) injury is a major cause of neonatal death and neurological dysfunction. H2S has been shown to protect against hypoxia-induced injury and apoptosis of neurons. L-Cysteine is catalyzed by cystathionine-β-synthase (CBS) in the brain and sequentially produces endogenous H2S. The present study was designed to investigate whether L-Cysteine could attenuate the acute brain injury and improve neurobehavioral outcomes following HI brain injury in neonatal mice by releasing endogenous H2S. L-Cysteine treatment significantly attenuated brain edema and decreased infarct volume and neuronal cell death, as shown by a decrease in the Bax/Bcl-2 ratio, suppression of caspase-3 activation, and reduced phosphorylation of Akt and ERK at 72 h after HI. Additionally, L-Cysteine substantially up-regulated NF-E2-related factor 2 and heme oxygenase-1 expression. L-Cysteine also decreased endoplasmic reticulum (ER) stress-associated pro-apoptotic protein expression. Furthermore, L-Cysteine had long-term effects by protecting against the loss of ipsilateral brain tissue and improving neurobehavioral outcomes. Importantly, pre-treatment with a CBS inhibitor significantly attenuated the neuroprotection of L-Cysteine on HI insult. Thus, L-Cysteine exerts neuroprotection against HI-induced injury in neonates via the CBS/H2S pathway, mediated in part by anti-apoptotic effects and reduced oxidative stress and ER stress. Thus, L-Cysteine may be a promising treatment for HI.

Purmorphamine Attenuates Neuro-Inflammation and Synaptic Impairments After Hypoxic-Ischemic Injury in Neonatal Mice via Shh Signaling

“…The Rice-Vannucci model was used to generate HI injury (Liu et al, 2017). Male C57BL/6J mouse pups on PND 7 were randomly selected.…”

“…The exploratory and anxiety-like behaviors of animals were assessed at 14 days post-HI in an open field test as described previously (Liu et al, 2017). Each mouse was placed in the corner of the box and allowed 5 min of exploration.…”

“…The spatial reference memory at 28 days post-HI was assessed using the MWM test as previously described (Liu et al, 2017). On training trials, the time required to locate and climb onto the platform (escape latency) was measured for 5 consecutive days (four trials/day).…”

“…For histological endpoint determinations, brains were harvested, fixed in 4% formaldehyde, and then sliced into 5 µm coronal sections in the region containing the infarct lesion (between −1.60 and −2.00 mm from bregma). Slices were then analyzed using Nissl staining, TUNEL staining, and immunofluorescence or immunohistochemical imaging (Liu et al, 2017). Analyses of the images were performed using the Image-Pro Plus 6.0 software by an investigator blinded as to experimental group assignments.…”

Prenatal electronic cigarette exposure decreases brain glucose utilization and worsens outcome in offspring hypoxic–ischemic brain injury

“…We applied the following exclusion criteria: severe weight loss, infections, or significant behavioral deficits (decreased mobility, seizures, lethargy). No pain medication was administered after surgery because the pups recovered naturally after returning back to their mothers and it is supported by other studies (Liu et al, 2017;Ten, Bradley-Moore, Gingrich, Stark, & Pinsky, 2003). 12 offspring pups were excluded from this study because of several weight loss & significant behavioral deficits and were sacrificed by isoflurane overdose which was confirmed by cervical dislocation.…”