The Novel Nitric Oxide Synthase Inhibitor 4-amino-tetrahydro-L-biopterine Prevents Brain Edema Formation and Intracranial Hypertension following Traumatic Brain Injury in Mice

Terpolilli, Nicole A.; Zweckberger, Klaus; Trabold, Raimund; Schilling, Lothar; Schinzel, Reinhard; Tegtmeier, F.; Plesnila, Nikolaus

doi:10.1089/neu.2008.0853

Cited by 53 publications

(21 citation statements)

References 66 publications

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“…Pharmacological inhibition of nNOS with 7-nitroindazole given 5 minutes after MCAo reduced infarct volume in rats by up to 27% Zhang et al, 1996b) and the application of aminoguanidine (Zhang et al, 1996a;Cash et al, 2001), N-3-(aminomethyl-benzyl)-acetamidine (Parmentier et al, 1999;Perez-Asensio et al, 2005), or 7-nitroindazol adduct 3-bromo-7-nitroindazole (Srinivasan and Sharma, 2012), all regarded as fairly selective iNOS inhibitors significantly reduced postischemic brain damage after transient and permanent cerebral ischemia. Similarly, noncompetitive NOS inhibitors, like the BH4 analog 4-amino-tetrahydro-L-biopterine, which putatively inhibit only newly formed NOS isoforms in vivo, that is, iNOS, reduced brain edema when applied after traumatic brain injury (Terpolilli et al, 2009). Another study reduced postischemic brain damage effectively by using antisense oligodeoxynucleotide to iNOS (Parmentier-Batteur et al, 2001).…”

Section: Nitric Oxide Synthase Inhibitorsmentioning

confidence: 99%

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Terpolilli¹,

Moskowitz

Plesnila³

2012

J Cereb Blood Flow Metab

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129

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Some 40 years ago it was recognized by Furchgott and colleagues that the endothelium releases a vasodilator, endothelium-derived relaxing factor (EDRF). Later on, several groups identified EDRF to be a gas, nitric oxide (NO). Since then, NO was identified as one of the most versatile and unique molecules in animal and human biology. Nitric oxide mediates a plethora of physiological functions, for example, maintenance of vascular tone and inflammation. Apart from these physiological functions, NO is also involved in the pathophysiology of various disorders, specifically those in which regulation of blood flow and inflammation has a key role. The aim of the current review is to summarize the role of NO in cerebral ischemia, the most common cause of stroke.

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Section: Nitric Oxide Synthase Inhibitorsmentioning

confidence: 99%

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Terpolilli¹,

Moskowitz

Plesnila³

2012

J Cereb Blood Flow Metab

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129

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“…Regional cerebral blood flow (rCBF) was measured by Laser Doppler Fluxmetry (Periflux 4001 Master, Perimed, Stockholm, Sweden) as previously described. [9][10][11] Intracranial pressure (ICP) was measured by an intraparenchymal probe (Mammendorfer Institut, Mammendorf, Germany) placed 2 mm right of the bregma. Blood samples (50 ml) were collected before trauma and at the end of the observation period for blood gas analysis.…”

Section: Anesthesia and Surgical Preparationmentioning

confidence: 99%

“…3,9,12 In brief, after craniotomy on the right parietal cortex an impactor tip (diameter 3 mm) was placed perpendicularly to the surface of the brain on the intact dura. The lesion was induced with a velocity of 8 m/s, with an impact depth of 1 mm and a contact time of 150 ms.…”

Section: Trauma Inductionmentioning

confidence: 99%

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Inhaled Nitric Oxide Reduces Secondary Brain Damage after Traumatic Brain Injury in Mice

Terpolilli¹,

Kim²,

Thal³

et al. 2012

J Cereb Blood Flow Metab

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Ischemia, especially pericontusional ischemia, is one of the leading causes of secondary brain damage after traumatic brain injury (TBI). So far efforts to improve cerebral blood flow (CBF) after TBI were not successful because of various reasons. We previously showed that nitric oxide (NO) applied by inhalation after experimental ischemic stroke is transported to the brain and induces vasodilatation in hypoxic brain regions, thus improving regional ischemia, thereby improving brain damage and neurological outcome. As regional ischemia in the traumatic penumbra is a key mechanism determining secondary posttraumatic brain damage, the aim of the current study was to evaluate the effect of NO inhalation after experimental TBI. NO inhalation significantly improved CBF and reduced intracranial pressure after TBI in male C57 Bl/6 mice. Long-term application (24 hours NO inhalation) resulted in reduced lesion volume, reduced brain edema formation and less blood-brain barrier disruption, as well as improved neurological function. No adverse effects, e.g., on cerebral auto-regulation, systemic blood pressure, or oxidative damage were observed. NO inhalation might therefore be a safe and effective treatment option for TBI patients.

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“…34,44 As a reference for the initial primary damage, these parameters also were assessed 15 min after trauma in each experimental series. At the respective end-point of the experiments, the animals were anesthetized with ketanest intraperitoneally and sacrificed by cervical dislocation.…”

Section: Histopathological Analysismentioning

confidence: 99%

The Formation of Microthrombi in Parenchymal Microvessels after Traumatic Brain Injury Is Independent of Coagulation Factor XI

Schwarzmaier

Chaumont

Balbi

et al. 2016

Journal of Neurotrauma

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Microthrombus formation and bleeding worsen the outcome after traumatic brain injury (TBI). The aim of the current study was to characterize these processes in the brain parenchyma after experimental TBI and to determine the involvement of coagulation factor XI (FXI). C57BL/6 mice (n = 101) and FXI-deficient mice (n = 15) were subjected to controlled cortical impact (CCI). Wild-type mice received an inhibitory antibody against FXI (14E11) or control immunoglobulin G 24 h before or 30 or 120 min after CCI. Cerebral microcirculation was visualized in vivo by 2-photon microscopy 2-3 h post-trauma and histopathological outcome was assessed after 24 h. TBI induced hemorrhage and microthrombus formation in the brain parenchyma ( p < 0.001). Inhibition of FXI activation or FXI deficiency did not reduce cerebral thrombogenesis, lesion volume, or hemispheric swelling. However, it also did not increase intracranial hemorrhage. Formation of microthrombosis in the brain parenchyma after TBI is independent of the intrinsic coagulation cascade since it was not reduced by inhibition of FXI. However, since targeting FXI has well-established antithrombotic effects in humans and experimental animals, inhibition of FXI could represent a reasonable strategy for the prevention of deep venous thrombosis in immobilized patients with TBI.

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The Novel Nitric Oxide Synthase Inhibitor 4-amino-tetrahydro-L-biopterine Prevents Brain Edema Formation and Intracranial Hypertension following Traumatic Brain Injury in Mice

Cited by 53 publications

References 66 publications

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

Inhaled Nitric Oxide Reduces Secondary Brain Damage after Traumatic Brain Injury in Mice

The Formation of Microthrombi in Parenchymal Microvessels after Traumatic Brain Injury Is Independent of Coagulation Factor XI

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