Effects of Moderate Hypothermia on Constitutive and Inducible Nitric Oxide Synthase Activities After Traumatic Brain Injury in the Rat

Abstract

Abstract:We investigated the effects of therapeutic hypothermia (30°C) on alterations in constitutive (cNOS) and inducible (iNOS) nitric oxide synthase activities following traumatic brain injury (TSI). Male Sprague-Dawley rats were anesthetized with 0.5% halothane and underwent moderate (1.8-2.2 atm) parasagittal fluid-percussion (F-P) brain injury. In normothermic rats (37°C) the enzymatic activity of cNOS was significantly increased at 5 min within the injured cerebral cortex compared with contralateral values (286.5 t 68.9% of contralateral value; mean ? SEM). This rise in nitric oxide synthase activity was significantly reduced with pretraumatic hypothermia (138.8 t 17% of contralateral value; p < 0.05). At 3 and 7 days after normothermic TBI the enzymatic activity of cNOS was decreased significantly (30 f 8.4 and 28.6 t 20.9% of contralateral value, respectively; p < 0.05). However, immediate posttraumatic hypothermia (3 h at 30°C) preserved cNOS activity at 3 and 7 days (69.5 f 23.3 and 78.6 ? 7.6% of contralateral value, respectively; mean ? SEM; p < 0.05). Posttraumatic hypothermia also significantly reduced iNOS activity at 7 days compared with normothermic rats (0.021 t 0.06 and 0.23 2 0.06 pmol/mg of proteidmin, respectively; p < 0.05). The present results indicate that hypothermia (a) decreases early cNOS activation after TBI, (b) preserves cNOS activity at later periods, and (c) prevents the delayed induction of iNOS. Temperature-dependent alterations in cNOS and iNOS enzymatic activities may participate in the neuroprotective effect of hypothermia in this TBI model. Key Words: Hypothermia-Nitric oxideConstitutive nitric oxide synthase-Inducible nitric oxide synthase-Fluid-percussion brain injury.

Pre-Hospital Hypothermia is Not Associated with Increased Survival After Traumatic Brain Injury

“…Experimental studies of post-traumatic hypothermia suggest a multitude of possible mechanisms for neuroprotection. These include reducing levels of the excitatory amino acid glutamate; decreasing abnormal blood-brain barrier permeability after traumatic and ischemic insults; inhibiting diffuse axonal injury; reducing proinflammatory cytokines interleukin 1-b and tumor necrosis factor-a; inhibiting apoptotic cell death by decreasing both cytochrome c release from dysfunctional mitochondria as well as levels of caspase, a significant initiator of apoptosis [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Additionally, TBI is often characterized by a postinjury catecholamine surge that correlates directly with the severity of brain injury [31][32][33].…”

Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

“…For example, the selective serotonin reuptake inhibitor sertraline protects against transient global ischemia-induced behavioral despair, and these beneficial effects are reversed by NO upregulation [97]. Hypothermia therapy also inhibits NO production during cerebral ischemia and upregulation of inducible nitric oxide synthase (iNOS), which might account, at least in part, for the neuroprotective effects of this treatment [98, 99]. In short, it appears that NO activation of the GC-PKG pathway may be deleterious, particularly when it leads to induction of iNOS, and some or most of these deleterious effects may be due to NO itself or its peroxide byproducts driven by iNOS.…”

Extraluminal Cooling of Bilateral Common Carotid Arteries as a Method to Achieve Selective Brain Cooling for Neuroprotection

“…The current strategies to treat brain trauma patients are predominantly supportive by decreasing intracranial pressure, providing airway ventilation or resuscitation, and stabilizing cardiovascular function. Hypothermia has also been used in patients with severe traumatic brain injury (TBI) to control refractory elevated intracranial pressure (Smrcka et al, 2005) and to limit the biochemical cascade that may lead to a secondary brain injury (Chatzipanteli et al, 1999). Numerous pre-clinical studies have shown that induced hypothermia is neuroprotective to improve outcomes after traumatic or ischemic brain injury in animal models by limiting the extent of brain injury and improving neurological and functional recovery (Barone et al, 1997).…”