The Effects of Tetrahydrobiopterin on Intracerebral Hemorrhage-Induced Brain Injury in Mice
Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase (NOS) and is presently used clinically to treat forms of phenylketonuria. BH4 has been reported to restrain superoxide generation of NOS and chemically reduce superoxide. However
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Abstract Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase (NOS) and is presently used clinically to treat forms of phenylketonuria. BH4 has been reported to restrain superoxide generation of NOS and chemically reduce superoxide. However, there has been no report concerning the effects of BH4 in intracerebral hemorrhage (ICH). In the present study, we investigated the neuroprotective effect of BH4 against ICH-induced brain injury in a mouse model. A total of 26 male CD1 mice (31–39 g) were divided into sham, ICH-vehicle, and ICH-treated with BH4 groups (n = 8 in each group). ICH was induced by collagenase injection into the right basal ganglia. BH4 (20 mg/kg) was administrated intraperitoneally at 1 h after ICH. The effect of BH4 was measured by neurological score and brain water content at 24 h after ICH. Our data demonstrates that ICH caused significant neurological deficit that is associated with brain edema. Treatment with BH4 did not reduce brain edema and neurological deficits at 24 h after ICH in mice. Further study is required to investigate the long-term effect of BH4 in ICH-induced brain injury. Keywords Tetrahydrobiopterin(BH4) • ICH • mice • brain edema
injury contributes to the poor clinical outcomes. Oxidative stress is considered a major contributor to ICH-induced secondary brain injury (1). Hemoglobin (Hb) autoxidation and the iron release due to hemoglobin degradation start a chain of Hb-driven oxidative reactions (1). Reactive oxygen species (ROS) including superoxide anion, hydrogen peroxide and peroxynitrite (ONOO-) are produced. In addition, it has been reported that the inducible NO synthase (NOS)-derived peroxynitrite (ONOO-) contributes to ischemic brain injury (6). Blockade of endogenous brain tetrahydrobiopterin (BH4) (an essential cofactor for NOS activity) synthesis attenuates cerebral infarction via inhibiting iNOS and ONOO- (6). It was described that formation of superoxide (14) and hydrogen peroxide (7) in part is controlled by BH4 and BH4 efficiently inhibits superoxide generation from the heme group at the oxygenase domain of eNOS (13). However, a possible role of BH4 in secondary brain injury after ICH has not been examined. The goal of the presented study was to test whether BH4 administration may reduce brain edema formation and thus reduce neurological deficit after ICH.
Materials and Methods
Introduction
Animal Preparation
Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke and carries high mortality and morbidity. Except the initial hemorrhagic impact, secondary brain
A total of 26 male CD1 mice (31–39 g) were divided into sham (n = 8), ICH-vehicle (n = 9), and ICH-treated with BH4 (n = 9). ICH was induced by collagenase injection into the right basal ganglia as described by Rosenberg et al. (8). (6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride (BH4, Sigma-Aldrich, St. Louis, MO) was administrated intraperitoneally at 1 h after ICH. All surgical procedures were approved by the Loma Linda University Institutional Comm
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