Biomedical subjects

Frederick Colbourne

Publications and source records attributed to Frederick Colbourne.

At least 19 recordsLinked to original sources

PubMed2006

Skilled reaching impairments follow intrastriatal hemorrhagic stroke in rats.

The infusion of autologous blood into the brain of rats is a widely used model of intracerebral hemorrhage (ICH). Careful assessment of functional recovery is an essential part of preclinical testing (e.g., putative cytoprotectants). However, few tests detect long-term deficits in this model. In this study, we used the staircase and single pellet tests to characterize skilled reaching ability after striatal ICH. Rats were trained to reach for food pellets in these tasks before ICH, which was created by infusing 100muL of autologous blood into the striatum. We assessed reaching success in both tasks for 5 days starting 7 and 28 days after ICH. We counted the number of reaching attempts made with each forelimb in the staircase task and performed kinematic analysis of reaching in the single pellet task. The contralateral (to lesion) forelimb reaching success was significantly impaired in the staircase task 1 week after ICH, but this recovered to pre-surgical levels thereafter. Reaching deficits in the single pellet task were more severe and persistent. Detailed analysis of reaches on day 11 revealed several abnormalities in the following movement components: pronation, grasping, supinating the paw and releasing the pellet. At 1 month, only digit opening and supination were impaired. Accordingly, the single pellet task is better at detecting long-term skilled reaching impairments in the whole blood model of ICH. Thus, the single pellet task seems suited to cytoprotection and rehabilitation studies.

Animals↗

PubMed2006

Forced exercise does not improve recovery after hemorrhagic stroke in rats.

Exercise can improve recovery following ischemia and intracerebral hemorrhage (ICH) in rodents. We tested whether forced exercise (EX; running wheel) prior to and/or following ICH in rats would reduce lesion volume and improve functional outcome (walking, skilled reaching, spontaneous paw usage) at 7 weeks post-ICH. A striatal hemorrhage was produced by infusing collagenase. First, we compared animals that received EX (2 weeks; 1 h/day) ending two days prior to ICH and/or starting two weeks following ICH. EX did not improve functional recovery or affect lesion size. Doubling the amount of EX given per day (two 1-h sessions) both prior to and following ICH did not alter lesion volume, but worsened recovery. We then determined if EX (1 h/day) prior to and following ICH would affect outcome after a somewhat milder insult. There were no differences between the groups in lesion volume or recovery. Finally, we used a hemoglobin assay at 12 h following ICH to determine if pre-stroke EX (2 weeks; 1 h/day) aggravated bleeding. It did not. These observations suggest that EX does not improve outcome when given prior to and/or when delayed following ICH. Effective rehabilitation for ICH will likely require more complex interventions than forced running.

Analysis of Variance↗

PubMed2006

A simple method to induce focal brain hypothermia in rats.

Hypothermia reduces cell death and promotes recovery in models of cerebral ischemia, intracerebral hemorrhage and trauma. Clinical studies report significant benefit for treating cardiac arrest and studies are investigating hypothermia for stroke and related conditions. Both local (head) and generalized hypothermia have been used. However, selective brain cooling has fewer side effects than systemic cooling. In this study, we developed a method to induce local (hemispheric) brain hypothermia in rats. The method involves using a small metal coil implanted between the Temporalis muscle and adjacent skull. This coil is then cooled by flushing it with cold water. In our first experiment, we tested whether this method induces focal brain hypothermia in anesthetized rats. Brain temperature was assessed in the ipsilateral cortex and striatum, and contralateral striatum, while body temperature was kept normothermic. Focal, ipsilateral cooling was successfully produced, while the other locations remained normothermic. In the second experiment, we implanted the coil, and brain and body temperature telemetry probes. The coil was connected via overhead swivel to a cold-water source. Brain hypothermia was produced for 24 h, while body temperature remained normothermic. A third experiment measured brain and body temperature along with heart rate and blood pressure. Brain cooling was produced for 24 h without significant alterations in pressure, heart rate or body temperature. In summary, our simple method allows for focal brain hypothermia to be safely induced in anesthetized or conscious rats, and is, therefore, ideally suited to stroke and trauma studies.

Anesthesia↗

PubMed2006

The influence of hypothermia on outcome after intracerebral hemorrhage in rats.

BACKGROUND AND PURPOSE: Late hypothermia (HYPO) reduces injury after collagenase-induced intracerebral hemorrhage (ICH), whereas early HYPO does not because it exacerbates the protracted bleeding that occurs in this model. We hypothesized that early HYPO would not increase bleeding after whole blood infusion and thus expected early HYPO to improve outcome through reducing secondary consequences of ICH (eg, inflammation). METHODS: Autologous blood (100 microL) was infused into the striatum. Rats were maintained at normothermia or subjected to mild (33 degrees C to 35 degrees C) HYPO for 2 days starting 1 (HYPO-1) or 4 hours (HYPO-4) after ICH. Hematoma volume was measured at 12 hours to determine whether HYPO-1 aggravated bleeding. We measured blood-brain barrier (BBB) disruption and edema 2 days after ICH in all groups. At 4 days, we counted degenerating neurons, neutrophils, and iron-positive cells (eg, macrophages) in the lesioned hemisphere. Recovery was assessed using several behavioral tests (ie, staircase reaching task, ladder walking task, limb use cylinder test) over 7 or 30 days, at which time we quantified lesion volume. RESULTS: HYPO did not increase bleeding. Both HYPO treatments reduced BBB disruption and infiltration of inflammatory cells. HYPO-1 treatment modestly reduced edema and provided limited to no functional benefit in the behavioral tests. HYPO did not affect lesion volume. CONCLUSIONS: HYPO reduced edema, BBB disruption, and inflammation. Although encouraging, HYPO treatment must be improved so that histological and functional benefit are obtained before clinical investigation. Otherwise clinical failure is anticipated.

Animals↗

PubMed2005

Gauging recovery after hemorrhagic stroke in rats: implications for cytoprotection studies.

Successful clinical translation of prospective cytoprotectants will likely occur only with treatments that improve functional recovery in preclinical (rodent) studies. Despite this assumption, many rely solely on histopathologic end points or the use of one or two simple behavioral tests. Presently, we used a battery of tests to gauge recovery after a unilateral intracerebral hemorrhagic stroke (ICH) targeting the striatum. In total, 60 rats (N=15 per group) were stereotaxically infused with 0 (SHAM), 0.06 (MILD lesion), 0.12 (MODERATE lesion), or 0.18 U (SEVERE lesion) of bacterial collagenase. This created a range of injury akin to moderate (from SEVERE to MODERATE or MODERATE to MILD lesion size approximately 30% reduction) and substantial cytoprotection (SEVERE to MILD lesion size--51% reduction). Post-ICH functional testing occurred over 30 days. Tests included the horizontal ladder and elevated beam tests, swimming, limb-use asymmetry (cylinder) test, a Neurologic Deficit Scale, an adhesive tape removal test of sensory neglect, and the staircase and single pellet tests of skilled reaching. Most tests detected significant impairments (versus SHAM), but only a few (e.g., staircase) frequently distinguished among ICH groups and none consistently differentiated among all ICH groups. However, by using a battery of tests we could behaviorally distinguish groups. Thus, preclinical testing would benefit from using a battery of behavioral tests as anything less may miss treatment effects. Such testing must be based on factors including the type of lesion, the postoperative delay and the time required to complete testing.

Animals↗

PubMed2005

17beta-Estradiol pretreatment reduces bleeding and brain injury after intracerebral hemorrhagic stroke in male rats.

17beta-estradiol reduces cell death after global and focal ischemia and subarachnoid hemorrhage in rodents. Presently, we tested whether estrogen improves outcome after intracerebral hemorrhage (ICH) in male rats. Rats were implanted subcutaneously with 0.05, 0.25, or 0.50 mg pellets of estrogen (21-day release) or subjected to a sham procedure. Two weeks after implantation, they were given a striatal ICH via an infusion of collagenase. The three estrogen groups had significantly smaller lesions at a 7-day survival. Some rats had core temperature measured with an implanted telemetry probe, which also measured whole-body movements. Estrogen did not affect temperature nor activity levels after ICH. A second study with 0.25 mg pellets, administered once or twice, showed persistent histologic protection (30 days) and some functional benefit (e.g., elevated beam). A spectrophotometric hemoglobin assay showed that the 0.25 mg dose significantly reduced hemorrhagic blood volume at 12 hours after ICH. Regardless, estrogen did not lessen cerebral edema at 2 days after ICH and functional benefits were not consistently found on all tests (e.g., cylinder task). In summary, estrogen pretreatment reduces injury after ICH, in part by reducing bleeding. Estrogen may thus lessen injury and improve outcome after ICH in humans.

Animals↗

PubMed2005

Mild to moderate hyperthermia does not worsen outcome after severe intracerebral hemorrhage in rats.

Hyperthermia worsens outcome in clinical and experimental studies of ischemic stroke. Thus, we tested whether hyperthermia aggravates intracerebral hemorrhage (ICH) in rats. A striatal hemorrhage was produced via an infusion of bacterial collagenase. In a preliminary experiment, we compared brain and core temperatures (via telemetry) during heating (infrared lamp). The brain temperature rise exceeded that produced by enforced core hyperthermia, which was used subsequently. In these experiments up to three hyperthermia conditions (versus normothermia) were tested including: hyperthermia (>38.5 degrees C) over the first (HYP-1) or second 24 h period (HYP-2) after ICH and 3 h of 40 degrees C hyperthermia starting 12 h after ICH (HYP-3). The HYP-1, HYP-2, and HYP-3 treatments did not affect functional deficits (e.g., spontaneous forelimb use, skilled reaching) or the volume of injury at 30 days. Furthermore, the HYP-1 treatment did not aggravate injury or deficits at 7 days. Bleeding and inflammation, which contribute to pathology, were not significantly altered by HYP-1 and HYP-3 treatments. Bleeding was assessed at 1 day, and macrophages and neutrophils were counted at 2 and 4 days. Accordingly, hyperthermia, under the present conditions, did not worsen outcome after striatal ICH.

Animals↗

PubMed2005

Increased behavioral and histological variability arising from changes in cerebrovascular anatomy of the Mongolian gerbil.

The Mongolian gerbil (Meriones unguiculatus) has been used extensively as a model of forebrain ischemia. Its unique susceptibility to ischemia was suggested to be due to an incomplete circle of Willis. The relative ease to which ischemia can be induced combined with highly reproducible delayed CA1 cell death following a 5 min occlusion made the model popular in neuroprotection studies. Presently, this assumption was tested that complete forebrain ischemia occurs in all gerbils because increased variability was noticed in neuronal injury and behavioral outcome using this model in the last several years. Here it is reported that gerbils obtained from Charles River, the largest supplier in North America, show a high incidence (22.7% with bilateral and 38.6% with unilateral anastomoses) of posterior communicating arteries compared to another supplier of gerbils (High Oak Farms, 2.6% with bilateral and 13.2% with unilateral anastomoses, P<0.0001). This increased incidence of complete or partial circle of Willis led to less severe CA1 cell loss in Charles River gerbils (P<0.0001) compared to High Oak gerbils, with an unacceptably high level of inter-animal variability. Similarly, behavioral indices of CA1 ischemic injury (increased locomotion, habituation deficits) were also significantly attenuated in the Charles River animals. High Oak gerbils also displayed increased histological and behavioral variability relative to the pattern obtained several years ago. Thus, the gerbil model of forebrain ischemia, at least using Charles River animals, no longer produces consistent injury and behavioral alterations. Investigators are urged to consider adopting other models in future neuroprotection studies or ensure that their gerbil population lacks communicating arteries.

Animals↗

PubMed2004

Post-ischemic diazepam does not reduce hippocampal CA1 injury and does not improve hypothermic neuroprotection after forebrain ischemia in gerbils.

The hippocampal CA1 sector is especially vulnerable to brief forebrain ischemia. Excitotoxicity is widely thought to contribute to this cell death. Accordingly, drugs that presumably counteract excitotoxicity, such as GABAergic agonists, have been repeatedly tested and found to reduce CA1 cell loss. Post-ischemic diazepam reduces CA1 injury. However, diazepam also causes hypothermia, which by itself is neuroprotective. Most studies fail to adequately control for this confound. In this study, we tested whether diazepam reduces injury in temperature controlled gerbils subjected to brief forebrain ischemia. Furthermore, we tested whether diazepam augments hypothermic neuroprotection. All gerbils were implanted with a core temperature telemetry probe and a cannula for the subsequent insertion of a thermocouple probe to measure ischemic brain temperature. Subsequently, they were given a 5-min normothermic ischemic insult. In Experiment 1, two groups of gerbils were given 10 mg/kg doses of diazepam (i.p.) at both 30 and 90 min post-ischemia. Temperature was maintained in one group by heating lamps. Another group was administered saline. Diazepam reduced cell death at 7 days post-ischemia when the drug-induced hypothermia was permitted, but not when it was prevented. In Experiment 2, four groups of ischemic gerbils were treated starting at 12 h post-ischemia with prolonged hypothermia, diazepam and the combination or saline treatment. Hypothermia, but not diazepam, provided partial neuroprotection and diazepam did not augment hypothermic neuroprotection. Thus, neuroprotection with diazepam is solely due to hypothermia. These data do not support the clinical use of diazepam as a neuroprotectant after global ischemia.

Animals↗

PubMed2004

Temperature-regulated model of focal ischemia in the mouse: a study with histopathological and behavioral outcomes.

BACKGROUND AND PURPOSE: The importance of mouse stroke models has increased with the development of genetically manipulated animals. We hypothesized that immediate postischemia hypothermia may attenuate ischemic brain injury in the mouse. METHODS: Intraabdominal radio frequency probes were implanted in animals and core temperature monitored. Groups included: MCAO-45-REG (45 minutes middle cerebral artery occlusion [MCAO]) temperature-controlled in the postischemic period >34 degrees C for 24 hours; MCAO-45 (45 minutes MCAO) were allowed to self-regulate core temperature during recovery; MCAO-30-REG (30 minutes MCAO), with the same temperature protocol as MCAO-45-REG; MCAO-30 (30 minutes MCAO), with temperature protocol the same as MCAO-45. Behavior and histological score was assessed at 7 days. The qualitative histological score assessed for injury in 18 specified regions. RESULTS: MCAO-45-REG core temperature (mean 34.94 degrees C+/-0.8 degrees C) was significantly different than the self-regulating (MCAO-45, mean 33.1 degrees C+/-2.3 degrees C) for the first 4 hours after anesthesia (P<0.01). There was a trend toward similar differences in temperatures for MCAO-30-REG and MCAO-30 (P=0.08). At 7 days, a greater improvement in behavior score was observed for MCAO-45 and MCAO-30 compared with MCAO-45-REG and MCAO-30-REG (P<0.001). The histological score confirmed reduced injury in unregulated temperature groups (MCAO-45-REG mean 38+/-10 and MCAO-45 30+/-5.1, P<0.05; MCAO-30-REG 41+/-10 and MCAO-30 30+/-9, P<0.05). CONCLUSIONS: Hypothermia is an important confounder of stroke injury in the intraluminal filament mouse model. Future mouse stroke studies must use strict temperature regulation.

Animals↗

PubMed2004

Delayed onset of prolonged hypothermia improves outcome after intracerebral hemorrhage in rats.

Prolonged hypothermia reduces ischemic brain injury, but its efficacy after intracerebral hemorrhagic (ICH) stroke is unresolved. Rats were implanted with core temperature telemetry probes and subsequently subjected to an ICH, which was produced by infusing bacterial collagenase into the striatum. Animals were kept normothermic (NORMO), or were made mildly hypothermic (33-35 degrees C) for over 2 days starting 1 hour (HYP-1), 6 hours (HYP-6), or 12 hours (HYP-12) after collagenase infusion. Others were cooled for 7 hours beginning 1 hour after infusion (BRIEF). Skilled reaching, walking, and spontaneous forelimb use were assessed. Normothermic ICH rats sustained, on average, a 36.9-mm3 loss of tissue at 1 month. Only the HYP-12 group had a significantly smaller lesion (25.5 mm3). Some functional improvements were found with this and other hypothermia treatments. Cerebral edema was observed in NORMO rats, and was not lessened significantly by hypothermia (HYP-12). Blood pressure measurements, as determined by telemetry, in BRIEF rats showed that hypothermia increased blood pressure. This BRIEF treatment also resulted in significantly more bleeding at 12 hours after ICH (79.2 microL) versus NORMO-treated rats (58.4 microL) as determined by a spectrophotometric hemoglobin assay. Accordingly, these findings suggest that early hypothermia may fail to lessen lesion size owing to complications, such as elevated blood pressure, whereas much-delayed hypothermia is beneficial after ICH. Future experiments should assess whether counteracting the side effects of early hypothermia enhances protection.

Animals↗

PubMed2004

Immediate constraint-induced movement therapy causes local hyperthermia that exacerbates cerebral cortical injury in rats.

Constraint-induced movement therapy (CIMT), which involves restraint of the nonimpaired arm coupled with physiotherapy for the impaired arm, lessens impairment and disability in stroke patients. Surprisingly, immediate ipsilateral forelimb immobilization exacerbates brain injury in rats. We tested whether immediate ipsilateral restraint for 7 days aggravates injury after a devascularization lesion in rats. Furthermore, we hypothesized that ipsilateral restraint aggravates injury by causing hyperthermia. In experiment 1, each rat received two lesions, one in the motor cortex and one in the visual cortex. Ipsilateral restraint increased only the motor cortex lesion. In additional rats, no differences in core temperature occurred after ipsilateral or contralateral restraint. Thus, ipsilateral restraint does not aggravate injury by a systemic side effect. In experiment 2, we hypothesized that ipsilateral restraint causes hyperthermia in the region surrounding the initial cortical lesion. Brain temperature, measured via telemetry, was significantly higher (approximately 1 degrees C for 24 h) with ipsilateral restraint. A third experiment similarly found that ipsilateral restraint aggravates injury and causes local cortical hyperthermia and that contralateral restraint with externally induced mild hyperthermia aggravates injury. In conclusion, immediate ipsilateral restraint aggravates injury apparently by localized events that include hyperthermia. Caution must be exercised in applying early CIMT to humans, as hyperthermia is detrimental.

Animals↗

PubMed2003

Constraint-induced movement therapy and rehabilitation exercises lessen motor deficits and volume of brain injury after striatal hemorrhagic stroke in rats.

BACKGROUND AND PURPOSE: Constraint-induced movement therapy (CIMT) promotes motor recovery after occlusive stroke in humans, but its efficacy after intracerebral hemorrhage (ICH) has not been investigated clinically or in the laboratory. In this study we tested whether CIMT and a rehabilitation exercise program would lessen motor deficits after ICH in rats. METHODS: Rats were subjected to striatal ICH (via infusion of collagenase) or sham stroke. Seven days later, treatment began with CIMT (8 h/d of ipsilateral forelimb restraint), rehabilitation exercises (eg, reaching, walking; 1 h/d), or both for 7 days. Some rats were not treated. Motor deficits were assessed up to the 60-day survival time, after which the volume of tissue lost was determined. RESULTS: Untreated ICH rats made more limb slips traversing a horizontal ladder and showed an asymmetry toward less use of the contralateral paw in the cylinder test of limb use asymmetry (day 28). These rats were also significantly less successful in the Montoya staircase test (days 55 to 59) of skilled reaching. Neither therapy alone provided much benefit. However, the combination of daily exercises and CIMT substantially and persistently improved recovery. Unexpectedly, this group had a statistically smaller volume of tissue lost than untreated ICH rats. CONCLUSIONS: The combination of focused rehabilitation exercises and CIMT effectively promotes functional recovery after ICH, while either therapy alone is less effective. This therapy may work in part by reducing the volume of tissue lost, likely through reducing atrophy while promoting remodeling.

Animals↗

PubMed2003

A robust, efficient and flexible method for staining myelinated axons in blocks of brain tissue.

Previous studies have demonstrated the utility of the gold chloride method for en bloc staining of a bisected brain in mice and rats. The present study explores several variations in the method, assesses its reliability, and extends the limits of its application. We conclude that the method is very efficient, highly robust, sufficiently accurate for most purposes, and adaptable to many morphometric measures. We obtained acceptable staining of commissures in every brain, despite a wide variety of fixation methods. One-half could be stained 24 h after the brain was extracted and the other half could be stained months later. When staining failed because of an exhausted solution, the brain could be stained successfully in fresh solution. Relatively small changes were found in the sizes of commissures several weeks after initial fixation or staining. A half brain stained to reveal the mid-sagittal section could then be sectioned coronally and stained again in either gold chloride for myelin or cresyl violet for Nissl substance. Uncertainty, arising from pixelation of digitized images was far less than errors arising from human judgments about the histological limits of major commissures. Useful data for morphometric analysis were obtained by scanning the surface of a gold chloride stained block of brain with an inexpensive flatbed scanner.

Animals↗

PubMed2003

Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia.

Brief forebrain ischemia in rodents induces selective and delayed neuronal death, particularly of hippocampal CA1 pyramidal neurons. Neuronal death is preceded by down-regulation specific to CA1 of GluR2, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit that limits Ca(2+) influx. This alteration is hypothesized to cause neurodegeneration by permitting a lethal influx of Ca(2+) and/or Zn(2+) through newly formed GluR2-lacking AMPA receptors. Two days of mild hypothermia induced 1 h after ischemia potently and lastingly protects against ischemic injury. We examined molecular mechanisms underlying hypothermia-induced neuroprotection. We report that hypothermia rescues most hippocampal CA1 neurons from ischemia-induced cell death and attenuates ischemia-induced down-regulation of mRNA encoding the AMPA receptor subunit GluR2. Ischemia induced a marked down-regulation of GluR2 mRNA and a small down-regulation of GluR1 mRNA in CA1 at 2 days, as assessed by quantitative in situ hybridization. The ischemia-induced changes in gene expression were cell-specific in that GluR2 was not significantly altered in CA3 or dentate gyrus. After ischemia treated by hypothermia GluR2 mRNA expression was modestly reduced at 2 days and exhibited complete recovery to control levels at 7 days. Hypothermia prevented ischemia induced changes in GluR1 mRNA expression. These findings suggest that intervention at the level of transcriptional regulation of the GluR2 gene may be a mechanism by which prolonged postischemic cooling rescues CA1 neurons otherwise "destined to die."

Animals↗

PubMed2003

Delayed transient ischemic attacks kill some CA1 neurons previously salvaged with postischemic hypothermia: neuroprotection undone.

Delayed hypothermia reduces ischemic hippocampal CA1 injury. However, there are residual structural and functional abnormalities. Therefore, we studied whether these apparently vulnerable rescued neurons are susceptible to secondary insults. All gerbils were subjected to normothermic forebrain ischemia (ISC, 5 min) or SHAM operation. Gerbils were treated with mild hypothermia (HYPO; 33 degrees C for 24 h+35 degrees C for 24 h) beginning 12 h after surgery, or they remained normothermic (NORMO). Then 5 and 6 days following ISC/SHAM operation gerbils received sublethal transient ischemic attacks (TIA, 1.5 min) or sham (SH) surgeries. Behavioral testing was done and animals survived for 30 days for quantification of medial, middle and lateral CA1 sector cell death. The SHAM groups were not significantly different. The ISC+NORMO+SH group lost 87.3% (of SHAM) of medial CA1 neurons, which was not significantly exacerbated in the ISC+NORMO+TIA group (91.1%, P=0.633). However, the ISC+HYPO+TIA group (58.8% loss) had significantly more cell death than the ISC+HYPO+SH group (42.8%; P=0.035), although CA1 protection was still better than in ISC+NORMO groups (P<0.001). Trends were similar in middle and lateral CA1, but the deleterious effects of TIAs were not statistically significant. Behavioral testing did not distinguish groups with or without TIA, but did reveal deficits in ISC+NORMO groups and protection in ISC+HYPO groups. These data, like previous ultrastructural findings, show that while most hypothermia-rescued CA1 neurons are healthy, some are susceptible. Perhaps other neuroprotectants, especially weaker ones, might be undone by delayed insults (e.g. TIA, fever).

Animals↗

PubMed2003

Brain temperature measurement and regulation in awake and freely moving rodents.

Temperature measurement and control are essential in most ischemia experiments. Hypothermia lessens ischemic brain injury whereas hyperthermia exacerbates it. A substantial number of ischemia studies rely solely on rectal temperature measurements during the insult. However, rectal temperature may not accurately reflect brain temperature especially during global ischemia. Furthermore, postischemic temperature changes are often inadequately monitored. Delayed cooling reduces injury, whereas delayed hyperthermia aggravates it. This review summarizes our experiences with core and brain telemetry probes to continually measure temperature in various ischemia models. Furthermore, we discuss methods to simultaneously measure and regulate temperature in the freely moving postischemic rodent, and the need for such control in ischemia research.

Animals↗

PubMed2003

Incomplete assessment of experimental cytoprotectants in rodent ischemia studies.

BACKGROUND: Inadequate preclinical testing (e.g., rodent studies) has been partly blamed for the failure of many cytoprotectants to effectively treat stroke in humans. For example, some drugs went to clinical trial without rigorous functional and histological assessment over long survival times. In this study, we characterized recent experimental practices in rodent cytoprotection experiments to determine whether the limitations of early studies have been rectified. METHODS: We identified 138 rodent cytoprotection studies published in several leading journals (Journal of Neuroscience, Stroke, Journal of Cerebral Blood Flow and Metabolism and Experimental Neurology) for 2000-2002 and compared these to those published in 1990. From each study we determined the ischemia model, age and sex of the animal, the histological and functional endpoints used, and the methodology used to assess intra- and postischemic temperature. RESULTS: Ninety-eight percent of recent studies used young adult rodents and most used males. Most studies (60%) did not assess functional outcome and survival times were often < or = 48 hr (66%) for focal ischemia and < or = 7 days (80%) for global ischemia. Over 60% of the experiments relied solely upon rectal temperature during ischemia and only 32.6% of ischemia studies measured temperature after surgery. The 1990 data were similar. CONCLUSIONS: Many investigators ignore the need to assess long-term functional and histological outcome and do not accurately represent clinical conditions of ischemia (e.g., use of aged animals). In addition, intra- and postischemic temperature measurement and control is frequently neglected or inadequately performed. Further clinical failures are likely.

Animals↗