Biomedical subjects

Michael R Hoane

Publications and source records attributed to Michael R Hoane.

14 recordsLinked to original sources

PubMed2006

The effects of nicotinamide on apoptosis and blood-brain barrier breakdown following traumatic brain injury.

Nicotinamide has been shown to protect against many of the pathophysiological factors associated with both ischemic and traumatic brain injuries. The present study evaluated the neuroprotective effect of nicotinamide on the breakdown of the blood-brain barrier (BBB) and apoptosis expression following traumatic brain injury (TBI). Animals were prepared with a unilateral cortical contusion injury (CCI). Fifteen minutes following injury the animals received either nicotinamide (500 mg/kg, ip) or 0.9% saline. The animals were perfused at 5, 24, and 72 h post-injury. BBB integrity was assessed by endogenous rat IgG immunoreactivity. Recent studies have shown that IgG immunoreactivity is a reliable measure of BBB integrity. The results indicated that IgG immunoreactivity was greatest at 5 h and declined at 24 h after injury. Nicotinamide significantly reduced IgG expression at every time point following injury. Apoptosis was examined using the TUNEL method. The results indicated that TUNEL immunoreactivity peaked at 24 h. TUNEL(+) cells were classified morphologically as nonapoptotic (Type I) or apoptotic (Type II) to verify that the neuroprotective effects of nicotinamide occur by inhibiting apoptosis or necrosis. Administration of nicotinamide significantly reduced the expression of all TUNEL(+) cells in the tissue surrounding the lesion cavity. Specifically there was a significant reduction in the number of Type I, Type II, and Total TUNEL(+) cells in the nicotinamide-treated animals. In addition, nicotinamide reduced lesion cavity expansion 72 h following CCI. These findings suggest that nicotinamide reduces BBB breach and neuronal cell loss acutely following injury and that these reductions may account for the beneficial behavioral effects seen in previous studies.

Analysis of Variance↗

PubMed2006

Nicotinamide reduces acute cortical neuronal death and edema in the traumatically injured brain.

Previous studies have shown that administration of nicotinamide (Vitamin B(3)) in animal models of traumatic brain injury (TBI) and ischemia significantly reduced the size of infarction or injury and improved functional recovery. The present study evaluated the ability of nicotinamide to provide acute neuroprotection and edema reduction following TBI. Groups of rats were assigned to nicotinamide (500mg/kg) or saline (1.0ml/kg) treatment conditions and received contusion injuries or sham surgeries. Drug treatment was administered 15min following injury. Brains were harvested 24h later and either processed for histology or water content. Frozen sections were stained with the degenerating neuron stain (Fluoro-Jade B) (FJ) and cell counts were performed at the site of injury. Additional brains were processed for water content (a measure of injury-induced edema). Results of this study showed that administration of nicotinamide following TBI significantly reduced the number of FJ(+) neurons in the injured cortex compared to saline-treated animals. Examination of the water content of the brains also revealed that administration of nicotinamide significantly attenuated the amount of water compared to saline-treated animals in the injured cortex. These results indicate that nicotinamide administration significantly reduced neuronal death and attenuated cerebral edema following injury. The current findings suggest that nicotinamide significantly modulates acute pathophysiological processes following injury and that this may account for its beneficial effects on recovery of function following injury.

Animals↗

PubMed2006

Administration of raloxifene reduces sensorimotor and working memory deficits following traumatic brain injury.

Hormonal differences between males and females have surfaced as a crucial component in the search for effective treatments after experimental models of traumatic brain injury (TBI). Recent findings have shown that selective estrogen receptor modulators (SERMs) may have therapeutic benefit. The present study examined the effects of raloxifene, a SERM, on functional recovery after bilateral cortical contusion injury (bCCI) or sham procedure. Male rats received injections of raloxifene (3.0mg/kg, i.p.) or vehicle (1.0 ml/kg, i.p.) 15 min, 24, 48, 72, and 96 h after bCCI or sham procedure. Rats were tested on both sensorimotor (bilateral tactile removal and locomotor placing tests) and cognitive tests (reference and working memory in the Morris water maze). Raloxifene-treated animals showed a significant reduction in the initial magnitude of the deficit and facilitated the rate of recovery for the bilateral tactile removal test, compared to vehicle-treated animals. The raloxifene-treated animals also showed a significant improvement in the acquisition of working memory compared to vehicle-treated animals. However, raloxifene did not significantly improve the acquisition of reference memory or locomotor placing ability. Raloxifene treatment also did not result in a significant reduction in the size of the lesion cavity. Thus, the task-dependent improvements seen following raloxifene treatment do not appear to be the result of cortical neuroprotection. However, these results suggest that raloxifene improves functional outcome following bCCI and may present an interesting avenue for future research.

Analysis of Variance↗

PubMed2006

Magnesium and riboflavin combination therapy following cortical contusion injury in the rat.

Previous research has shown that magnesium chloride (MgCl(2)) and riboflavin (B(2)) both significantly improve functional recovery when administered shortly after frontal cortical contusion injury (CCI). The purpose of the present study was to examine the ability of combination treatments of MgCl(2) and B(2) to improve functional outcome following unilateral CCI. One hour post-injury, rats were administered MgCl(2) (1.0 mmol/kg), B(2) (7.5mg/kg), MgCl(2)+B(2) (1 mmol/kg+7.5mg/kg), 1/2 MgCl(2)+1/2 B(2) (0.5 mmol/kg and 3.75 mg/kg), or saline. Two days following CCI rats were tested on a battery of sensorimotor (vibrissae-->forelimb placing and tactile removal test) and motor (staircase test). A regimen of MgCl(2)+B(2) significantly reduced the initial impairment and facilitated the rate of recovery on the tactile removal test and facilitated the rate of recovery on the forelimb placing test. The half-dose combination did not significantly improve functional recovery on the tactile removal test compared to the individual treatments; however, it did improve performance on the forelimb placing test compared to saline treatment. Administration of MgCl(2) improved performance on the placing and tactile removal tests on 2 post-operative days, as did treatment with B(2) on the tactile removal test. The results indicate that the full combination of MgCl(2)+B(2) significantly improved functional recovery to a greater extent than the individual treatments or the low dose combination group on forelimb placing but not on tactile removal. These findings suggest that administration of MgCl(2)+B(2) may provide better therapeutic action than individual treatments.

Analysis of Variance↗

PubMed2006

Nicotinamide treatment reduces behavioral impairments and provides cortical protection after fluid percussion injury in the rat.

This study examined the ability of nicotinamide (vitamin B3) to improve functional outcome in a dose-dependent manner following fluid percussion injury (FPI). Injured (duration of unconsciousness mean = 85.8 sec; apnea = 9.9 sec), rats were administered nicotinamide (500 or 50 mg/kg; ip) or saline at 15 min and 24 h. Serum analysis of nicotinamide concentrations were conducted 1 h following the last injection. Sensorimotor and cognitive tests were conducted for 35 days following FPI. Both the 500 and 50 mg/kg doses of nicotinamide significantly facilitated recovery on the vibrissae-forelimb placing test compared to saline treatment, which showed chronic impairments. Both treatments also significantly improved performance on the bilateral tactile adhesive removal test. On the cognitive tests, the 500 mg/kg dose, but not the 50 mg/kg dose, improved performance on a working memory task in the Morris water maze (MWM). However, acquisition of a reference memory task in the MWM was not improved. Serum analysis showed that the 500 mg/kg dose significantly raised nicotinamide concentrations by 30-fold and the 50 mg/kg dose by 3-fold compared to the saline administration. This study demonstrated that raising nicotinamide concentrations resulted in the reduction of the behavioral impairments following FPI. In fact, the 500 mg/kg dose prevented the occurrence of the behavioral deficits on the bilateral tactile removal and working memory tests. Both doses significantly reduced tissue loss and glial fibrillary acid protein (GFAP) expression in the cortex. The 500 mg/kg dose reduced GFAP expression in the hippocampus. This data suggests that nicotinamide has substantial preclinical efficacy for TBI, and there appears to be some differences in the ability of the doses to improve performance in the MWM.

Animals↗

PubMed2005

Administration of riboflavin improves behavioral outcome and reduces edema formation and glial fibrillary acidic protein expression after traumatic brain injury.

Previous studies have shown that administration of riboflavin, vitamin B2, significantly reduced edema formation following experimental stroke. The present study evaluated the ability of B2 to improve behavioral function, reduce edema formation, and limit glial fibrillary acidic protein (GFAP) expression following frontal cortex contusion injury. Groups of rats were assigned to B2 (7.5 mg/kg) or saline (1.0 ml/kg) treatment conditions and received contusion injuries or sham procedures. Drug treatment was administered 15 min and 24 h following injury. Rats were examined on a variety of tests to measure sensorimotor performance (bilateral tactile removal test), and cognitive ability (acquisition of reference and working memory) in the Morris water maze. Administration of B2 following injury significantly reduced the behavioral impairments observed on the bilateral tactile removal test and improved the acquisition of both reference and working memory tests compared to saline-treated rats. The lesion analysis showed that B2 reduced the size of the lesion. Examination of GFAP expression around the lesion revealed that B2 significantly reduced the number of GFAP+ astrocytes. Edema formation following injury was also significantly reduced by B2 administration. These findings are the first to show that B2 administration significantly improved behavioral outcome and reduced lesion volume, edema formation, and the expression of GFAP following traumatic brain injury. These findings suggest that B2 may have therapeutic potential for the treatment of TBI.

Animals↗

PubMed2005

Treatment with magnesium improves reference memory but not working memory while reducing GFAP expression following traumatic brain injury.

PURPOSE: Previous studies have shown that administration of MgCl2 in animal models of brain injury significantly improves functional recovery: however, few studies have examined cognitive recovery. The present study evaluated the effect of MgCl2 pharmacotherapy on recovery of function following medial frontal cortex contusion injury. METHODS: Groups of rats were assigned to either MgCl2 (1.0 mmol/kg) or saline treatment conditions and prepared with contusion injuries or shams. Drug treatment was administered 15 min and 24 hr following injury. Rats were examined on tests of sensorimotor performance (bilateral tactile adhesive removal) and cognitive ability (reference and working memory). RESULTS: Administration of MgCl2 following injury significantly reduced the behavioral impairments observed on the bilateral tactile removal test. The acquisition of reference memory was also significantly improved compared to saline-treated rats; however, treatment did not improve working memory performance. Lesion analysis revealed that administration of MgCl2 did not significantly reduce lesion size compared to saline-treatment. Examination of glial fibrillary acidic protein (GFAP) expression showed that MgCl2 did significantly reduce the number of GFAP+ cells. CONCLUSION: These results indicate that MgCl2 administration significantly improved behavioral outcome following injury in a task dependent manner and reduced GFAP expression.

Animals↗

PubMed2004

Middle age increases tissue vulnerability and impairs sensorimotor and cognitive recovery following traumatic brain injury in the rat.

With increasing age comes an increased risk for sustaining traumatic brain injuries (TBI). However, the effect of age is rarely studied in animal models of TBI. The present study evaluated the effect of increased age on recovery of function following bilateral medial frontal cortex injury. Groups of young (3 months) and middle-aged (14 months) rats received bilateral frontal cortex contusions or sham injuries. The rats were tested on a variety of tests to measure sensorimotor performance (bilateral tactile adhesive removal test), skilled forelimb use (staircase test), and the acquisition of reference and working memory in the Morris water maze. Results indicated that injury produced significant impairments on all behavioral tests compared to sham controls. Middle-aged rats that received cortical contusions were significantly impaired on the bilateral tactile adhesive removal test, acquisition of a reference memory task, and working memory compared to young-injured rats. Histological analysis showed that middle-aged rats developed significantly larger lesion cavities but did not show an increase in the number of glial fibrillary acidic protein (GFAP+) cells compared to young-injured rats. Age alone also significantly impaired function on the bilateral adhesive tactile removal test, skilled forelimb use, the acquisition of a reference memory task, and also increased the number of GFAP+ cells compared to young rats. These results indicate that middle-aged rats respond to brain injury differently than young rats and that age is an important factor to consider in pre-clinical efficacy studies.

Age Factors↗

PubMed2004

Transplantation of neuronal and glial precursors dramatically improves sensorimotor function but not cognitive function in the traumatically injured brain.

Embryonic stem (ES) cells have been investigated in various animal models of neurodegenerative disease; however, few studies have examined the ability of ES cells to improve functional outcome following traumatic brain injury (TBI). The purpose of the present study was to examine the ability of pre-differentiated murine ES cells (neuronal and glial precursors) to improve functional outcome. Rats were prepared with a unilateral controlled cortical impact injury or sham and then transplanted 7 days later with 100K ES cells (WW6G) (~30% neurons) or media. Two days following transplantation rats were tested on a battery of behavioral tests. It was found that transplantation of ES cells improved behavioral outcome by reducing the initial magnitude of the deficit on the bilateral tactile removal and locomotor placing tests. ES cells also induced almost complete recovery on the vibrissae --> forelimb placing test, whereas, media-transplanted rats failed to show recovery. Acquisition of a reference memory task in the Morris water maze was not improved by transplantation of ES cells. Histological analysis revealed a large number of surviving ES cells in the lesion cavity and showed migration of ES cells into subcortical structures. It was found that transplantation of ES cells prevented the occurrence of multiple small necrotic cavities that were seen in the cortex adjacent to the lesion cavity in media transplanted rats. Additionally, ES cells transplants also significantly reduced lesion size. Results of this study suggest that ES cells that have been pre-differentiated into neuronal precursors prior to transplantation have therapeutic potential.

Animals↗

PubMed2004

Magnesium therapy and recovery of function in experimental models of brain injury and neurodegenerative disease.

The role of magnesium (Mg(2+)) in brain injury has been well established. The present paper reviews the use of Mg(2+) therapy to facilitate recovery of function in a focal model of brain injury. Specifically a summary of the ability of magnesium chloride (MgCl(2)) to induce recovery of chronic behavioral impairments and the establishment of MgCl(2)'s wide therapeutic window is presented. These results suggest that Mg(2+) therapy is effective in facilitating recovery of function and exhibits very robust and unique effects.

Animals↗

PubMed2003

The behavioral effects of magnesium therapy on recovery of function following bilateral anterior medial cortex lesions in the rat.

Magnesium (Mg(++)) therapy has been shown to be neuroprotective and to facilitate recovery of motor and sensorimotor function in a variety of animal models of traumatic brain injury. However, few studies have investigated the efficacy of Mg(++) therapy on cognitive impairments following injury. The present study evaluated the ability of magnesium chloride (MgCl(2)) to facilitate recovery of function following bilateral anterior medial cortex lesions (bAMC). Rats received electrolytic bAMC lesions or sham surgery and were then treated with 1 mmol/kg, i.p. MgCl(2), 2 mmol/kg, i.p. MgCl(2), or 1.0 ml/kg, i.p. 0.9% saline. Drug treatment was administered 15 min following injury with subsequent injections administered at 24 and 72 h. Rats were tested on a battery of behavioral tests that measured both cognitive (reference and working memory in the Morris Water Maze (MWM) and spatial delayed matching-to-sample (DMTS)) and sensorimotor performance (bilateral tactile adhesive removal). The results indicated that bAMC lesions produced significant cognitive impairments in reference memory and working memory in the MWM, DMTS and sensorimotor impairments compared to shams. Mg(++) therapy exhibited a dose-dependent effect in facilitating recovery of function. Administration of 2mmol of MgCl(2) significantly improved performance on the bilateral adhesive tactile removal test, DMTS and working memory tests. The 1 mmol dose of MgCl(2) reduced the initial deficit on the tactile adhesive removal test and reduced the working memory impairment on the second day of testing. These results suggest Mg(++) therapy improves cognitive performance following injury in a dose-dependent manner.

Analysis of Variance↗

PubMed2003

Treatment with vitamin B3 improves functional recovery and reduces GFAP expression following traumatic brain injury in rats.

Previous studies have shown that administration of vitamin B(3) (B(3)) in animal models of ischemia significantly reduced the size of infarction and improved functional recovery. The present study evaluated the effect of administration of B(3) on recovery of function following traumatic brain injury (TBI), incorporating the bilateral medial frontal cortex contusion injury model. Groups of rats were assigned to B(3) (500 mg/kg) or saline (1.0 ml/kg) treatment conditions and received contusion injuries or sham surgeries. Drug treatment was administered 15 min and 24 h following injury. Rats were examined on a variety of tests to measure sensorimotor performance (bilateral tactile adhesive removal), skilled forelimb use (staircase test), and cognitive ability (reference and working memory) in the Morris Water Maze. Administration of B(3) following injury significantly reduced the behavioral impairments observed on the bilateral tactile removal test, but not on skilled forelimb use. The acquisition of reference and working memory tests were also significantly improved compared to saline-treated rats. Examination of the brains revealed that administration of B(3) significantly reduced the size of the lesion compared to treatment with saline. In addition, examination of glial fibrillary acidic protein (GFAP) expression around the lesion revealed that B(3) significantly reduced the number of GFAP(+) astrocytes. These results indicate that B(3) administration significantly improved behavioral outcome following injury, reduced the size of the lesion, and reduced the expression of GFAP. The current findings suggest that B(3) may have therapeutic potential for the treatment of TBI.

Animals↗

PubMed2002

The window of opportunity for administration of magnesium therapy following focal brain injury is 24 h but is task dependent in the rat.

The present study was conducted to establish the window of opportunity for the administration of a regimen of MgCl2 pharmacotherapy following focal injury to the brain. Rats were subjected to unilateral electrolytic lesions of the sensorimotor cortex (SMC) and administered a regimen of MgCl2 (1.0 mmol/kg) or 0.9% saline (1.0 ml/kg) beginning either 15 min, 8 h or 24 h after injury. Subsequent injections were administered 24 and 72 h after the initial treatment. Behavioral testing assessed recovery of function on several sensorimotor behaviors for 24 days following injury. The results of the present study suggest that treatment with a regimen of MgCl2 significantly facilitated recovery of function on the forelimb-->forelimb and vibrissae-->forelimb placing tests when administered 15 min, 8 h or 24 h after injury compared with saline-treated rats. Recovery of locomotor placing was significantly facilitated at 15 min and 8 h but not at 24 h compared with saline-treated rats. In addition, the ability of MgCl2 to limit neuronal loss in the ipsilateral ventral posterior lateral (VPL) nucleus of the thalamus was seen at only the 15-min treatment interval. These results suggest that the window of opportunity for MgCl2 pharmacotherapy is 24 h, task dependent and is much shorter for protecting neurons in the VPL.

Animals↗

PubMed2002

No detectable analgesic effects in the formalin test even with one million bovine adrenal chromaffin cells.

The present experiments were conducted to identify analgesic agents for transfection into immortalized adrenal chromaffin cell lines to maximize their analgesic potential. Analgesic agents known to be produced by adrenal chromaffin cells were infused intrathecally at a low dose (0.2 microg) which might conceivably be attained by adrenal chromaffin cell transplants. Numerous agents, administered individually and in two-factor combinations, produced significant analgesic effects in the formalin test. Before assessing the potential additive or synergistic effects of these analgesic agents with adrenal chromaffin cells, studies were conducted to demonstrate analgesic effects with adrenal chromaffin cells alone. Analgesic effects were previously reported in the literature with 80-100k intrathecal bovine adrenal chromaffin (BAC) cells; but in the present study 500k purified BAC cells failed to produce detectable analgesic effects. One million purified BAC cells also failed to produce analgesic effects in the formalin test. In a final study, even nicotine-stimulated release from one million purified BAC cells failed to produce analgesic effects in the formalin test. The fact that even one million nicotine-stimulated BAC cells failed to demonstrate therapeutic potential in these blinded experiments under conditions which were clearly sensitive to the analgesic agents produced by BAC cells, raises serious questions about the clinical utility of this experimental treatment.

Analgesics↗