Robert Vink

Magnesium protects against neurological deficit after brain injury

The biochemical factors that mediate secondary or delayed damage to the central nervous system (CNS) remain speculative. We have recently demonstrated that brain injury in rats causes a rapid decline in brain intracellular free magnesium (Mg2+) and total magnesium concentrations that is significantly correlated with the severity of injury. In order to further investigate the relationship between Mg2+ and brain injury, we examined the effect of Mg2+ treatment on posttraumatic neurological outcome following fluid-percussion brain injury (2.0 atm) in rats. Since administration of ATP-MgCl2 has been shown to be beneficial in a variety of models of organ ischemia, we also examined the efficacy of ATP-MgCl2 or ATP alone in the treatment of experimental brain injury. Animals treated with low (12.5 mumol) or high (125 mumol) dose MgCl2 at 30 min postinjury showed a significant dose-dependent improvement in neurological function when compared to saline-treated controls. Treatment with ATP-MgCl2 (12.5 mumol) or ATP alone (12.5 mumol) caused no significant improvement in chronic neurological outcome. MgCl2-treated animals showed no change in postinjury mean arterial blood pressure (MAP), whereas animals treated with either ATP-MgCl2 or ATP alone showed a transient but significant fall in MAP (P less than 0.01) during the drug-infusion period. Our results suggest that postinjury treatment with MgCl2 is effective in limiting the extent of neurological dysfunction following experimental traumatic brain injury in the rat.

Traumatic brain injury and Alzheimer's disease: a review

In an effort to identify the factors that are involved in the pathogenesis of Alzheimers disease (AD), epidemiological studies have featured prominently in contemporary research. Of those epidemiological factors, accumulating evidence implicates traumatic brain injury (TBI) as a possible predisposing factor in AD development. Exactly how TBI triggers the neurodegenerative cascade of events in AD remains controversial. There has been extensive research directed towards understanding the potential relationship between TBI and AD and the putative influence that apolipoprotein E (APOE) genotype has on this relationship. The aim of the current paper is to provide a critical summary of the experimental and human studies regarding the association between TBI, AD and APOE genotype. It will be shown that despite significant discrepancies in the literature, there still appears to be an increasing trend to support the hypothesis that TBI is a potential risk factor for AD. Furthermore, although it is known that APOE genotype plays an important role in AD, its link to a deleterious outcome following TBI remains inconclusive and ambiguous.

Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments

Purpose of reviewAlthough a number of factors contribute to the high mortality and morbidity associated with traumatic brain injury (TBI), the development of cerebral edema with brain swelling remains the most significant predictor of outcome. The present review summarizes the most recent advances in the understanding of mechanisms associated with development of posttraumatic cerebral edema, and highlights areas of therapeutic promise. Recent findingsDespite the predominance of cytotoxic (or cellular) edema in the first week after traumatic brain injury, brain swelling can only occur with addition of water to the cranial vault from the vasculature. As such, regulation of blood–brain barrier permeability has become a focus of recent research seeking to manage brain edema. Aquaporins, matrix metalloproteinases and vasoactive inflammatory agents have emerged as potential mediators of cerebral edema following traumatic brain injury. In particular, kinins (bradykinins) and tachykinins (substance P) seem to play an active physiological role in modulating blood–brain barrier permeability after trauma. Substance P neurokinin-1 receptor antagonists show particular promise as novel therapeutic agents. SummaryAttenuating blood–brain barrier permeability has become a promising approach to managing brain edema and associated swelling given that increases in cranial water content can only be derived from the vasculature. Inflammation, both classical and neurogenic, offers a number of attractive targets.

Effect of Noncompetitive Blockade of N‐Methyl‐d‐Aspartate Receptors on the Neurochemical Sequelae of Experimental Brain Injury

Abstract: Pharmacological inhibition of excitatory neurotransmission attenuates cell death in models of global and focal ischemia and hypoglycemia, and improves neurological outcome after experimental spinal cord injury. The present study examined the effects of the noncompetitive N‐methyl‐d‐aspartate receptor blocker MK‐801 on neurochemical sequelae following experimental fluid‐percussion brain injury in the rat. Fifteen minutes after fluid‐percussion brain injury (2.8 atmospheres), animals received either MK‐801 (1 mg/ kg, i.v.) or saline. MK‐801 treatment significantly attenuated the development of focal brain edema at the site of injury 48 h after brain injury, significantly reduced the increase in tissue sodium, and prevented the localized decline in total tissue magnesium that was observed in injured tissue of saline‐treated animals. Using phosphorus nuclear magnetic resonance spectroscopy, we also observed that MK‐801 treatment improved brain metabolic status and promoted a significant recovery of intracellular free magnesium concentrations that fell precipitously after brain injury. These results suggest that excitatory amino acid neurotransmitters may be involved in the pathophysiological sequelae of traumatic brain injury and that noncompetitive N‐methyl‐d‐aspartate receptor antagonists may effectively attenuate some of the potentially deleterious neurochemical sequelae of brain injury.

Soluble amyloid precursor protein α reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats

Amyloid precursor protein (APP) has previously been shown to increase following traumatic brain injury (TBI). Whereas a number of investigators assume that increased APP may lead to the production of neurotoxic Abeta and be deleterious to outcome, the soluble alpha form of APP (sAPPalpha) is a product of the non-amyloidogenic cleavage of amyloid precursor protein that has previously been shown in vitro to have many neuroprotective and neurotrophic functions. However, no study to date has addressed whether sAPPalpha may be neuroprotective in vivo. The present study examined the effects of in vivo, posttraumatic sAPPalpha administration on functional motor outcome, cellular apoptosis, and axonal injury following severe impact-acceleration TBI in rats. Intracerebroventricular administration of sAPPalpha at 30 min posttrauma significantly improved motor outcome compared to vehicle-treated controls as assessed using the rotarod task. Immunohistochemical analysis using antibodies directed toward caspase-3 showed that posttraumatic treatment with sAPPalpha significantly reduced the number of apoptotic neuronal perikarya within the hippocampal CA3 region and within the cortex 3 days after injury compared to vehicle-treated animals. Similarly, sAPPalpha-treated animals demonstrated a reduction in axonal injury within the corpus callosum at all time points, with the reduction being significant at both 3 and 7 days postinjury. Our results demonstrate that in vivo administration of sAPPalpha improves functional outcome and reduces neuronal cell loss and axonal injury following severe diffuse TBI in rats. Promotion of APP processing toward sAPPalpha may thus be a novel therapeutic strategy in the treatment of TBI.

The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats

Experimental models of traumatic brain injury have been developed to replicate selected aspects of human head injury, such as contusion, concussion, and/or diffuse axonal injury. Although diffuse axonal injury is a major feature of clinical head injury, relatively few experimental models of diffuse traumatic brain injury (TBI) have been developed, particularly in smaller animals such as rodents. Here, we describe the pathophysiological consequences of moderate diffuse TBI in rats generated by a newly developed, highly controlled, and reproducible model. This model of TBI caused brain edema beginning 20 min after injury and peaking at 24 h post-trauma, as shown by wet weight/dry weight ratios and diffusion-weighted magnetic resonance imaging. Increased permeability of the blood-brain barrier was present up to 4 h post-injury as evaluated using Evans blue dye. Phosphorus magnetic resonance spectroscopy showed significant declines in brain-free magnesium concentration and reduced cytosolic phosphorylation potential at 4 h post-injury. Diffuse axonal damage was demonstrated using manganese-enhanced magnetic resonance imaging, and intracerebral injection of a fluorescent vital dye (Fluoro-Ruby) at 24-h and 7-day post-injury. Morphological evidence of apoptosis and caspase-3 activation were also found in the cerebral hemisphere and brainstem at 24 h after trauma. These results show that this model is capable of reproducing major biochemical and neurological changes of diffuse clinical TBI.

Estrogen improves biochemical and neurologic outcome following traumatic brain injury in male rats, but not in females

Phosphorus magnetic resonance spectroscopy was used in conjunction with neurologic motor function tests to assess the effects of estrogen on biochemical and neurologic outcome following traumatic brain injury in male and female rats. Male (n = 18) and female (n = 18) rats were randomly assigned into three groups, and 4 h prior to injury received either 17 beta-estradiol (144 micrograms/kg intraperitoneally), equal volume vehicle (30% ethanol in saline), or no treatment. Traumatic brain injury was induced at 2.8 atm using a fluid percussion injury device, and animals monitored for 4 h using phosphorus magnetic resonance spectroscopy to determine brain intracellular pH, free magnesium concentration and cytosolic phosphorylation potential. Males treated with estrogen demonstrated a significant improvement in free magnesium concentration, and slightly improved values of cytosolic phosphorylation potential after trauma when compared to controls. There was also a significant improvement in post-traumatic motor function at 1 week after trauma. In contrast, estrogen treatment in females lowered cytosolic phosphorylation potential after trauma, but did not affect free magnesium concentration after trauma. Mortality in all female groups was significantly worse than in males. We conclude that estrogen is protective in males, but exacerbates brain injury in females through effects mediated by estrogen receptor binding.

Multifunctional drugs for head injury

SummaryTraumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.

Substance P is associated with the development of brain edema and functional deficits after traumatic brain injury

Brain edema and swelling is a critical factor in the high mortality and morbidity associated with traumatic brain injury (TBI). Despite this, the mechanisms associated with its development are poorly understood and interventions have not changed in over 30 years. Although neuropeptides and neurogenic inflammation have been implicated in peripheral edema formation, their role in the development of central nervous system edema after brain trauma has not been investigated. This study examines the role of the neuropeptide, substance P (SP), in the development of edema and functional deficits after brain trauma in rats. After severe diffuse TBI in adult male rats, neuronal and perivascular SP immunoreactivity were increased markedly. Perivascular SP colocalized with exogenously administered Evans blue, supporting a role for SP in vascular permeability. Inhibition of SP action by administration of the neurokinin-1 (NIC,) antagonist, N-acetyl-l-tryptophan, at 30 mins after trauma attenuated vascular permeability and edema formation. Administration of the NIC, antagonist also improved both motor and cognitive neurologic outcomes. These findings suggest that SP release is integrally linked to the increased vascular permeability and edema formation after brain trauma, and that treatment with an NIC, receptor antagonist reduces edema and improves neurologic outcome.

Both estrogen and progesterone attenuate edema formation following diffuse traumatic brain injury in rats.

Females have reduced brain edema compared to males after experimental brain trauma, although contradictory reports exist as to whether this is due to either estrogen or progesterone. In the present study, we demonstrate in both male and ovariectomized female rats that a single physiological dose of either hormone at 30 min after diffuse traumatic brain injury reduces both blood brain barrier permeability and edema formation. We conclude that both hormones may contribute to reduce edema in females after brain injury.