Deanne L. Heath

Neurogenic inflammation is associated with development of edema and functional deficits following traumatic brain injury in rats

The present study has used capsaicin-induced neuropeptide depletion to examine the role of neurogenic inflammation in the development of edema and functional deficits following traumatic brain injury (TBI). Adult, male rats were treated with capsaicin (neuropeptide-depleted) or equal volume vehicle (controls) 14 days prior to induction of moderate/severe diffuse TBI. Injury in vehicle treated control animals resulted in acute (4-5 h) edema formation, which was confirmed as being vasogenic in origin by diffusion weighted magnetic resonance imaging and the presence of increased permeability of the blood-brain barrier (BBB) to Evans blue dye. There was also a significant decline in brain magnesium concentration, as assessed by phosphorus magnetic resonance spectroscopy, and the development of profound motor and cognitive deficits. In contrast, capsaicin pre-treatment resulted in a significant reduction in post-traumatic edema formation (p < 0.001), BBB permeability (p < 0.001), free magnesium decline (p < 0.01) and both motor and cognitive deficits (p < 0.001). We conclude that neurogenic inflammation may play an integral role in the development of edema and functional deficits following TBI, and that neuropeptides may be a novel target for development of interventional pharmacological strategies.

Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats

Although a number of studies have demonstrated that magnesium improves acute motor and cognitive outcome after traumatic brain injury, others have failed to show positive effects on cognitive outcome and none have examined persistent functional deficits. The present study shows that severe impact-acceleration induced, diffuse traumatic brain injury in rats produced profound motor and cognitive deficits that persisted for at least 4 weeks after trauma. Intravenous administration of magnesium sulfate (250 micromoles/kg) at 30 min after injury significantly improved rotarod (sensorimotor) and open field (stress/anxiety) performance, and led to a faster rate of recovery in the Barnes maze (learning). We conclude that posttraumatic magnesium administration attenuates long-term motor and cognitive deficits after traumatic brain injury, and that this improvement may include some reduction of post-traumatic stress and anxiety.

Acute and Prolonged Alterations in Brain Free Magnesium Following Fluid Percussion-Induced Brain Trauma in Rats

Abstract: Several studies have reported declines in brain total and free magnesium concentration after a traumatic insult to the CNS. Although the evidence suggests that this magnesium decline is associated with eventual neurologic outcome after trauma, the duration of free magnesium decline and its impact on related bioenergetic variables are relatively unknown. The present study has therefore used phosphorus magnetic resonance spectroscopy to determine the length of time that free magnesium remains suppressed after traumatic brain injury in rats. Immediately after the traumatic event, brain intracellular free magnesium declined to <60% of preinjury values and remained significantly depressed (50 ± 8%; p < 0.001) for 5 days before recovering to preinjury levels by day 8. Cytosolic phosphorylation ratio and mitochondrial oxidative capacity also significantly decreased (p = 0.008) and increased (p = 0.002), respectively, after trauma. However, unlike the time of maximum magnesium change, the maximum changes in these bioenergetic variables occurred at 16–24 h after trauma and thereafter remained stable until after the magnesium had recovered. We conclude that free magnesium decline after trauma precedes changes in bioenergetic variables. Furthermore, therapies targeted at reestablishing magnesium homeostasis after trauma may require administration over a 1‐week period.

Magnesium attenuates post-traumatic depression/anxiety following diffuse traumatic brain injury in rats

Objective: Magnesium (Mg) declines after traumatic brain injury (TBI), a decline believed associated with ensuing neuronal cell death and subsequent functional impairment. While Mg’s effects on motor and cognitive deficits following TBI have been well studied, few studies have addressed post-traumatic depression as an outcome parameter, despite its being a major clinical problem with an incidence of between 6 and 77%. We investigated the incidence of post-traumatic depression/anxiety in an animal model of diffuse TBI, and explored the use of magnesium sulfate (MgSO4) as an interventional treatment. Methods: Diffuse TBI was induced in 32 anesthetized, adult, male Sprague-Dawley rats, using the 2 m impact-acceleration model of injury. At 30 min after injury, half of the rats received 250 μmol/kg i.v. MgSO4; the other half served as non-treated controls. Before and for 6 weeks after injury, the open-field, spontaneous activity test was used to determine post-traumatic depression/anxiety relative to pre-injury. In this test, animals are placed in a 1-meter square box with 100 squares marked on the base. The number of squares entered in a 5-min period is recorded. Incidence of post-traumatic depression/anxiety was defined as the number of animals demonstrating a reduction in spontaneous activity to less than 100 squares in 5 min. Prior to injury, rats typically entered a mean of 201 ± 12 (SEM) squares over a 5 min observation period. Results: At 1 week after injury, non-treated animals had a mean core of 62 ± 13. The incidence of post-traumatic depression/anxiety in these animals was 61%, which is similar to that observed clinically. In contrast, animals treated with MgSO4 had a mean activity score of 144 ± 23 at 1 week after TBI and an incidence of depression/anxiety of less than 30%. The significant difference between groups persisted for the entire 6-week observation period. Conclusions: The improvement in post-traumatic depression/anxiety conferred by Mg adds further weight to available evidence of Mg’s benefit as a neuroprotective agent after TBI.

Traumatic brain axonal injury produces sustained decline in intracellular free magnesium concentration

Decline in brain intracellular free magnesium concentration following experimental traumatic brain injury has been widely reported in a number of studies. However, to date, these studies have been confined to focal models of brain injury and temporally limited to the immediate 8-h period post-trauma. Recently, a new model of impact-acceleration brain injury has been developed which produces nonfocal diffuse axonal injury more typical of severe clinical trauma. The present study has used phosphorus magnetic resonance spectroscopy and the rotarod motor test to characterise magnesium homeostasis and neurologic outcome over a period of 8 days after induction of severe impact-acceleration injury in rats. Severe impact-acceleration induced injury resulted in a highly significant and sustained decline in intracellular free magnesium concentration that was apparent for 4 days post-trauma with recovery to preinjury levels by day six. There were no significant changes in pH or ATP concentration at any time point post-injury. All animals demonstrated a significant neurologic deficit over the assessment period. The extended period of magnesium decline after severe diffuse brain trauma suggests that repeated administration may be required for pharmacotherapies targeted at restoring magnesium homeostasis.

Magnesium sulphate improves neurologic outcome following severe closed head injury in rats

While recent evidence suggests that brain intracellular free magnesium concentration declines following severe diffuse traumatic brain injury, no studies have examined whether magnesium administration following such injury can improve subsequent neurologic outcome. The present study shows that MgSO4 administered as a bolus at 30 min following severe closed head injury in rats significantly improves posttraumatic neurologic outcome as assessed by both rotarod and angleboard tests. Moreover, this improvement in outcome was evident with both intravenous and intramuscular drug administration. We conclude that parenteral administration of magnesium sulphate may be neuroprotective following severe closed head injury of a diffuse nature.

Gestational Magnesium Deficiency Is Deleterious to Fetal Outcome

A number of recent epidemiological findings have implicated magnesium as being essential to fetal well-being. Few studies, however, have examined the relationship between maternal requirements for dietary magnesium and subsequent mortality and morbidity in offspring. The present study uses a rodent model of dietary-induced hypomagnesemia to investigate the effects of magnesium deficiency prior to and during gestation on neonatal morbidity and mortality. Magnesium deficiency during gestation significantly increased neonatal mortality and morbidity. Such increases were associated with a reduced free magnesium concentration in both maternal and offspring blood and an increased incidence of periventricular hemorrhage and edema in newborn pups as observed by magnetic resonance imaging and histology. Animals fed a magnesium-deficient diet before mating but given magnesium supplementation during gestation did not demonstrate a significant change in neonatal mortality and morbidity when compared to control animals. The significant improvement in fetal outcome with dietary magnesium supports the concept of magnesium supplementation during pregnancy.

Effects of daily versus weekly testing and pre-training on the assessment of neurologic impairment following diffuse traumatic brain injury in rats

A number of test paradigms have been used to determine acute and chronic motor and cognitive deficits after experimental traumatic brain injury (TBI). Some involve daily testing of either trained or untrained animals whereas others utilize periodic testing over extended time periods. Which test paradigm is the most appropriate for the assessment of motor and cognitive deficits is, however, unclear. In the current study, we have used both daily and weekly testing in trained and untrained animals to ascertain which assessment protocol is most suited for the detection of functional deficits after diffuse TBI in rats. Animals were subjected to severe injury using the impact-acceleration model of diffuse TBI. An equal number of animals were also prepared surgically but not subject to injury (shams). The rotarod device and the Barnes Maze were used for motor and cognitive assessment respectively, with half of the animals being pre-trained on each test for 10 days prior to injury. The open field test was used to assess spontaneous exploratory activity (stress). Following injury, animals were assessed for neurologic deficits either on a daily basis (for 10 days) or a weekly basis (for 4 weeks). In trained animals, the greatest differences in neurologic outcome between injured and sham animals were observed early after injury. In contrast, in untrained animals, greatest differences between injured and sham animals were observed at later time points. Pre-injury training did not improve the rate of cognitive recover, or the rate of motor recovery in the weekly test paradigm, but did improve the rate of motor recovery in the daily assessment paradigm. Daily assessment promoted rapid functional recovery whereas weekly assessments did not significantly affect outcome in injured animals over the 4-week assessment period. Spontaneous exploratory activity was decreased after TBI and was not influenced by task exposure. These studies demonstrate that the functional assessment paradigm needs to be considered when quantifying functional deficits following diffuse TBI in rats.

Factors to consider in smoking interventions for Indigenous women

More than 18,000 Australians die annually from diseases caused by tobacco. Indigenous Australians suffer a greater smoking-related disease burden than the remainder of the general public and have a higher prevalence of tobacco use than other Australians. The overall decline in smoking rates is slowest in women of low educational status between the ages of 25 -44. This is of particular concern as these young women may be pregnant or raising young children. During pregnancy, the effects on the foetus from cigarette smoke include respiratory illness, low birthweight and Sudden Infant Death Syndrome. However, if the mother is able to give up smoking by her fourth month of pregnancy, her risk of delivering a low birthweight baby decreases to nearly that of a non-smoker. As part of the planning to develop an effective smoking cessation program for young Indigenous pregnant women, the Townsville Aboriginal and Islanders Health Services (TAIHS) surveyed a group of women to assess smoking habits, attitudes to smoking, nicotine dependence and readiness for change. This paper reports on this survey and the results found can be used to develop a tailored, smoking cessation program for Indigenous women.

Subdural hematoma following traumatic brain injury causes a secondary decline in brain free magnesium concentration

A number of studies have demonstrated that neurologic motor and cognitive deficits induced by traumatic brain injury (TBI) can be attenuated with administration of magnesium salts. However, many severe traumatic brain injuries have a significant hematoma that develops subsequent to the primary events, and it is unclear whether magnesium salts are effective in this situation. In the present study, an impact-acceleration rodent model of TBI was used to produce an injury that causes an extensive subdural hematoma in over 50% of injured animals. At 30 min after TBI, rats were randomly administered 250 micromoles/kg intravenous MgSO4 or equal volume saline before being monitored by magnetic resonance spectroscopy for 8 h to determine brain intracellular free magnesium concentration. Animals were then assessed for neurologic motor deficits over 1 week using a rotarod device, followed by postmortem examination for presence of subdural hematoma. Animals with subdural hematoma treated with MgSO4 showed no improvement in motor outcome when compared to nontreated controls. Animals with no visible subdural hematoma demonstrated a significant improvement (p < 0.05 by ANOVA) in rotarod scores with MgSO4 treatment. Brain free magnesium concentration in the magnesium treated/hematoma group demonstrated a biphasic decline made up of an immediate initial decline, recovery of brain magnesium levels with MgSO4 treatment, and then a significant second magnesium decline (p < 0.05). Such a secondary decline did not occur in the Mg treated/no hematoma animals. Our results suggest that development of a subdural hematoma following TBI results in a decline in brain magnesium, even after bolus administration of magnesium salts. Such effects of hematoma development will need to be considered in trials examining efficacy of magnesium salts as an intervention following TBI.