Early reports of therapeutic hypothermia for severe traumatic brain injury can be traced back to the first half of the 20th century. It is only within the last two decades that clinical studies have demonstrated that therapeutic moderate hypothermia for brief durations can improve patient outcomes following brain injury. The historical background, recent clinical experience, and mechanisms of action of moderate hypothermia are reviewed.

https://www.nejm.org/doi/pdf/10.1056/NEJM199702203360803

Treatment of Traumatic Brain Injury with Moderate Hypothermia

Nitric oxide (NO) and reactive oxygen species exert multiple modulating effects on inflammation and play a key role in the regulation of immune responses. They affect virtually every step of the development of inflammation. Low concentrations of nitric oxide produced by constitutive and neuronal nitric oxide synthases inhibit adhesion molecule expression, cytokine and chemokine synthesis and leukocyte adhesion and transmigration. Large amounts of NO, generated primarily by iNOS can be toxic and pro-inflammatory. Actions of nitric oxide are however not dependent primarily on the enzymatic source, but rather on the cellular context, NO concentration (dependent on the distance from NO source) and initial priming of immune cells. These observations may explain difficulties in determining the exact role of NO in Th1 and Th2 lymphocyte balance in normal immune responses and in allergic disease. Similarly superoxide anion produced by NAD(P)H oxidases present in all cell types participating in inflammation (leukocytes, endothelial and other vascular cells etc) may lead to toxic effects, when produced at high levels during oxidative burst, but may also modulate inflammation in a far more discrete way, when continuously produced at low levels by NOXs (non-phagocytic oxidases). The effects of both nitric oxide and superoxide in immune regulation are exerted through multiple mechanisms, which include interaction with cell signalling systems like cGMP, cAMP, G-protein, JAK/STAT or MAPK dependent signal transduction pathways. They may also lead to modification of transcription factors activity and in this way modulate the expression of multiple other mediators of inflammation. Moreover genetic polymorphisms exist within genes encoding enzymes producing both NO and superoxide. The potential role of these polymorphisms in inflammation and susceptibility to infection is discussed. Along with studies showing increasing role of NO and free radicals in mediating inflammatory responses drugs which interfere with these systems are being introduced in the treatment of inflammation. These include statins, angiotensin receptor blockers, NAD(P)H oxidase inhibitors, NO-aspirin and others. In conclusion in this mini-review we discuss the mechanisms of nitric oxide and superoxide dependent modulation of inflammatory reactions in experimental animals and humans. We also discuss potential roles of nitric oxide as a mediator of allergic inflammation.

Nitric oxide and superoxide in inflammation and immune regulation.

Free radicals are highly reactive molecules implicated in the pathology of traumatic brain injury and cerebral ischemia, through a mechanism known as oxidative stress. After brain injury, reactive oxygen and reactive nitrogen species may be generated through several different cellular pathways, including calcium activation of phospholipases, nitric oxide synthase, xanthine oxidase, the Fenton and Haber-Weiss reactions, by inflammatory cells. If cellular defense systems are weakened, increased production of free radicals will lead to oxidation of lipids, proteins, and nucleic acids, which may alter cellular function in a critical way. The study of each of these pathways may be complex and laborious since free radicals are extremely short-lived. Recently, genetic manipulation of wild-type animals has yielded species that over- or under-express genes such as, copper-zinc superoxide dismutase, manganese superoxide dismutase, nitric oxide synthase, and the Bcl-2 protein. The introduction of the species has improved the understanding of oxidative stress. We conclude here that substantial experimental data links oxidative stress with other pathogenic mechanisms such as excitotoxicity, calcium overload, mitochondrial cytochrome c release, caspase activation, and apoptosis in central nervous system (CNS) trauma and ischemia, and that utilization of genetically manipulated animals offers a unique possibility to elucidate the role of free radicals in CNS injury in a molecular fashion.

Free Radical Pathways in CNS Injury

Objective:The purpose of this study was to compare the effects of two acute-care management strategies on the frequency of jugular venous desaturation and refractory intracranial hypertension and on long-term neurologic outcome in patients with severe head injury.Design:Randomized clinical trial.Set

Prevention of secondary ischemic insults after severe head injury.

https://www.redheracles.net/media/upload/research/pdf/161157211320677635.pdf

The physiology and pathophysiology of nitric oxide in the brain.

The effects of postinjury hypothermia on behavioral outcome following moderate fluid percussion traumatic brain injury (TBI) were examined. In Experiment I, three groups of rats were examined. The first group was normothermic (37.5°C); and hypothermia (30°C) was initiated 15 min and 30 min postinjury in the second and third groups, respectively. Whole body cooling was achieved by ventral ice pack. Cooling of the brain to 30°C was achieved in 25 min and maintained for 60 min. Brain temperature was measured indirectly by a probe in the temporalis muscle. Behavioral outcome was assessed by beam-balance performance, beam-walking performance, and body weight loss measured daily for 5 days after TBI. Both the normothermic group and the 30-min postinjury hypothermic group exhibited significant (p < 0.05) beam-balance and beam-walking deficits on days 1 through 5 after TBI. In contrast, the 15-min postinjury hypothermic group exhibited significant (p < 0.05) beamwalking deficits only on day 1 after TBI a...

Behavioral Protection by Moderate Hypothermia Initiated After Experimental Traumatic Brain Injury

Combined scopolamine and morphine treatment of traumatic brain injury in the rat.

We examined the effects of Nω-nitor-l-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), on mortality, morbidity, and cardiovascular parameters following traumatic brain injury (TBI) in the rat. Rats were anesthetized with 2% isoflurane prior to moderate (2.0 atmosphere), central fluid percussion TBI. Temporalis muscle temperature was maintained at 37±0.5°C. L-NAME (10 mg/kg iv) was administered once at either 5 min before, 5 min after, or 15 min after TBI. Sensorimotor deficits and spatial learning/ memory deficits were assessed after injury. Separate groups of rats were monitored for cardiovascular parameters. Preinjury administration of L-NAME significantly increased mortality from 13 (vehicle) to 70% (associated with pulmonary edema), whereas postinjury, L-NAME had no effect on mortality (14 and 25%). L-NAME adminstered at 5 or 15 min after injury had no significant effect on motor performance or cognitive performance deficits associated with TBI. L-NAME in uninjured rat increased arterial blood pressure by 25 mmHg within 2 min. L-NAME injected 5 min before TBI greatly prolonged the hypertensive episode associated with TBI (1 min in vehicle vs 60 min in L-NAME). L-NAME injected 5 min after TBI caused a sustained 35 mmHg increase in blood pressure. These findings suggest that acute inhibition of NOS has detrimental consequences on mortality that may be owing to its cardiovascular effects.

https://link.springer.com/content/pdf/10.1007/BF02815154.pdf

Inhibition of nitric oxide synthase potentiates hypertension and increases mortality in traumatically brain-injured rats

The magnitude of behavioral deficits in traumatic brain injury (TBI) has been shown to be partly related to alterations in the balance between excitatory and inhibitory neurotransmitter release. Previous studies have demonstrated that extracellular excitatory neurotransmitter concentrations dramatically increase following experimental TBI. We examined the effects of a neuromodulatory peptide, galanin (GAL), on behavioral morbidity, as measured by sensory motor and memory performance tasks, associated with experimental TBI in the rat. A single intraventricular injection of GAL (1.0 μg, n = 8 or 10.0 μg, n = 10) or cerebrospinal fluid (CSF) vehicle (n = 10) was administered 5 minutes prior to central fluid percussion TBI in rats. Performance on sensory motor tasks was assessed prior to injury and for 5 days after TBI with beam-balance, beam-walking, and rotarod tasks. Memory performance was assessed on days 11–15 after TBI with the Morris water maze. TBI produced significant motor and memory defici...

Shanliang Liu

Papers

Behavioral Protection by Moderate Hypothermia Initiated After Experimental Traumatic Brain Injury

Combined scopolamine and morphine treatment of traumatic brain injury in the rat.

Inhibition of nitric oxide synthase potentiates hypertension and increases mortality in traumatically brain-injured rats

Protective Effect of Galanin on Behavioral Deficits in Experimental Traumatic Brain Injury