Administration of S-methyl-l-thiocitrulline protects against brain injuries after intracerebral hemorrhage

Abstract

Although intracerebral hemorrhage (ICH) increases the level of glutamate in the perihematomal area and cerebral spinal fluid (CSF) in the ICH acute phase, it is unclear whether elevated glutamate activates neuronal nitric oxide synthase (nNOS) in the ICH brain and whether nNOS is an important target for ICH treatment. Here, we assessed the role of the nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) in the activity of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) and ICH-induced brain injuries. An autologous blood intracerebral infusion model in male rats was used. All of the rats were sacrificed 24 hours after ICH. ICH increased NADPH-d activity in the striatum. Administering SMTC 3 h after ICH decreased the activity of NADH-d (p < 0.05 vs. the ICH group). The activation of gelatinolytic enzymes in the perihematomal region of the striatum was reduced by SMTC treatment (p < 0.01, vs. the ICH group). The loss of laminin- and occludin-stained vessels was significant in perihematomal regions after 24 h of ICH and was significantly attenuated by the administration of SMTC (p < 0.01 for laminin, p < 0.05 for occluding, compared with the ICH group). Neuronal death and neurological deficits after ICH were also decreased in SMTC treatment rats (p < 0.01, vs. the ICH group). The results suggest that the administration of the nNOS inhibitor SMTC after ICH protects against ICH-induced brain injuries and improves neurological function.

Oxidative Stress in Intracerebral Hemorrhage: Sources, Mechanisms, and Therapeutic Targets

“…Other investigators detected NOS overexpression and suggested the role of the NOS/NO/ONOO − pathway in BBB disruption using the Hb-injection rat model [ 10 , 43 ]. In contrast, administering nNOS inhibitor after ICH was found to protect BBB integrity and decrease both neuronal death and neurological deficits [ 74 ]. Moreover, iNOS knockout mice present significantly less brain edema after collagenase-induced ICH [ 75 ].…”

“…Hemin also activates the NF- κ B transcription factor via an undefined mechanism [ 77 , 78 ]. In addition, high levels of glutamate activate NOS through the NMDA receptor with subsequent Ca 2+ influx by phosphorylating IKB and NF- κ B translocation [ 74 , 79 ].…”

NADPH Oxidase: A Potential Target for Treatment of Stroke

“…The activity of NOX enzymes increased significantly in hypertensive mice with spontaneous ICH [ 78 ]. A study also reported that activity of NADPH-d increased significantly in the rat striatum after ICH [ 79 ]. However, another study found that treatment with apocynin did not ameliorate the outcome of rats after ICH.…”