Journal of neurotrauma
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Journal of neurotrauma · Jul 1999
Differential effects of traumatic brain injury on vesicular acetylcholine transporter and M2 muscarinic receptor mRNA and protein in rat.
Experimental traumatic brain injury (TBI) produces cholinergic neurotransmission deficits that may contribute to chronic spatial memory deficits. Cholinergic neurotransmission deficits may result from presynaptic alterations in the storage and release of acetylcholine (ACh) or from changes in the receptors for ACh. The vesicular ACh transporter (VAChT) mediates accumulation of ACh into secretory vesicles, and the M2 muscarinic receptor subtype can modulate cholinergic neurotransmission via a presynaptic inhibitory feedback mechanism. ⋯ An increase in VAChT mRNA was also observed. Immunohistochemistry demonstrated a loss of M2; however, there was no significant change in M2 mRNA levels in comparison with sham controls. These changes may represent a compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission chronically after TBI through differential transcriptional regulation.
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Lubeluzole, a novel nitric oxide synthase (NOS) pathway modulator, was shown to be neuroprotective in cerebral ischemia as studied in animal models and clinical trials. The present study investigated the effect of lubeluzole on contusion volume and brain edema following traumatic brain injury. Sprague-Dawley rats (n = 36) were subjected to cortical impact injury. ⋯ T2-weighted MRI revealed a higher volume of edema at 90 minutes after trauma in treated rats. However, at 6 and 24 hours after trauma, no significant difference was discernible. Under these experimental conditions, lubeluzole fails to exert beneficial effects following experimental traumatic brain injury (TBI).
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Journal of neurotrauma · Jun 1999
Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury.
Recent observations concerning presumed calcium-induced mitochondrial damage and focal intraaxonal proteolysis in the pathogenesis of traumatic axonal injury (TAI) have opened new perspectives for therapeutic intervention. Studies from our laboratory demonstrated that cyclosporin A (CsA), a potent inhibitor of Ca2+-induced mitochondrial damage, administered 30 min prior to traumatic brain injury preserved mitochondrial integrity in those axonal foci destined to undergo delayed disconnection. We attributed this neuroprotection to the inhibition by CsA of mitochondrial permeability transition (MPT). ⋯ These results once again suggest that the maintenance of the functional integrity of the mitochondria can prevent TAI, presumably via the preservation of the local energy homeostasis of the axon. Moreover and perhaps more importantly, these studies also demonstrate the efficacy of CsA administration when given in the early posttraumatic period. Collectively, our findings suggest that a therapeutic window exists for the use of drugs targeting mitochondria and energy regulation in traumatic brain injury.
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Journal of neurotrauma · Jun 1999
Neuroprotective effect of hypothermia on neuronal injury in diffuse traumatic brain injury coupled with hypoxia and hypotension.
It is well established in mechanical head trauma that posttraumatic secondary insults, such as hypoxia and hypotension exacerbate neuronal injury and lead to worse outcome. In this study, the neuroprotective effect of hypothermia on the reduction of supraventricular subcortical neuronal damage was evaluated using an impact-acceleration model of diffuse traumatic brain injury coupled with both moderate and severe periods of hypoxia and hypotension. A total of 135 adult male Sprague-Dawley rats (340-375 g) were divided into three experimental studies: (I) physiological evaluation (n = 36); (II) quantitative analysis of the effect of trauma coupled with moderate and severe hypotension on neuronal damage assessed at 4 (n = 39) and 24 h (n = 24); and (III) the neuroprotective effect of hypothermia following moderate secondary insult (n = 36). ⋯ However, hypothermia provided nearly complete protection against secondary insults, and neuronal damage was equal to that of the trauma alone group (p = 0.42). The results of this study confirm that hypothermia provides remarkable protection against the adverse effects of neuronal damage exacerbated by secondary injury. This study also presents a new model of secondary insult, which can be used experimentally to further define the mechanism of increased vulnerability of the injured brain.
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Journal of neurotrauma · Jun 1999
Severity of experimental brain injury on lactate and free fatty acid accumulation and Evans blue extravasation in the rat cortex and hippocampus.
Lactate and free fatty acids (FFAs) were extracted from the cortices and hippocampi of rats subjected to sham operation, or mild (1.25 atm) or moderate (2.0 atm) fluid percussion (FP) injury, and their total tissue concentrations were measured. The elevation of lactate in the injured left cortex (IC) and ipsilateral hippocampus (IH) was significantly greater in the moderate-injury than in the mild-injury group at most test times between 5 min and 48 h after injury. Levels of total FFAs were elevated in the IC and IH to a greater extent and for a longer period after injury in the moderate-injury (up to 48 h) than in the mild-injury group (up to 20 min). ⋯ The extravasation of Evans blue in the IC and IH from 3 to 6 h after injury was also the greatest in the moderate-injury group. The hippocampal CA3 neuronal cell loss, but not cortical lesion volume, also increased with the severity of injury. These findings suggest that certain neurochemical, physiological (blood-brain barrier permeability), and morphologic responses increase with the severity of FP brain injury, and such relationships are consistent with the increased behavioral deficits observed with the increase of severity of brain injury.