Hyperthermic Rats Research Articles

Physicochemical Evaluation and Pharmacological Screening of Fernando Adenophylla Steenis Fruits.

The current study aimed to evaluate the physicochemical properties of Fernandoa adenophylla. Powder studies were carried out to estimate the quantitative physicochemical characteristics of the crude drug, including moisture content, ash content, and extractive values. Using a Soxhlet apparatus and different analytical grade solvents, 3 sample extracts of a crude drug were made. To evaluate the potentially toxic nature, an acute oral toxicity study was performed as per OECD guideline no. 423. Sample extracts were tested and analyzed by ANOVA for pharmacological potential (analgesic, antipyretic, and antidiabetic) using Wister-Albino rats. Where physicochemical analysis indicated purity, quality, and presence of organic/inorganic materials in crude drug extracts, no sign of mortality was found up to 2000 mg/kg of body weight of Fernandoa adenophyllas extracts. Analgesic activity was observed in all sample extracts, whereas only chloroform and ethanolic extracts expressed antipyretic and antidiabetic potential. Ethanolic extract was found to be most potent in pharmacological potential as 200 mg/kg extract dose exhibited %age pain inhibition of 55.12 % and reduced body temperature from 39.78±0.03 °C to 37.22±0.02 °C in hyperthermic rats. A decrease in blood glucose levels up to 57.88 % was observed on the 21st day of the treatment with 500 mg/kg ethanolic extract.

Core body temperatures of rats subjected to treadmill exercise to fatigue or exhaustion: The journal Temperature toolbox

ABSTRACT This study systematically reviewed the literature reporting the changes in rats’ core body temperature (TCORE) induced by either incremental- or constant-speed running to fatigue or exhaustion. In addition, multiple linear regression analyses were used to determine the factors contributing to the TCORE values attained when exercise was interrupted. Four databases (EMBASE, PubMed, SPORTDiscus, and Web of Science) were searched in October 2021, and this search was updated in August 2022. Seventy-two studies (n = 1,538 rats) were included in the systematic review. These studies described heterogeneous experimental conditions; for example, the ambient temperature ranged from 5 to 40°C. The rats quit exercising with TCORE values varying more than 8°C among studies, with the lowest and highest values corresponding to 34.9°C and 43.4°C, respectively. Multiple linear regression analyses indicated that the ambient temperature (p < 0.001), initial TCORE (p < 0.001), distance traveled (p < 0.001; only incremental exercises), and running speed and duration (p < 0.001; only constant exercises) contributed significantly to explaining the variance in the TCORE at the end of the exercise. In conclusion, rats subjected to treadmill running exhibit heterogeneous TCORE when fatigued or exhausted. Moreover, it is not possible to determine a narrow range of TCORE associated with exercise cessation in hyperthermic rats. Ambient temperature, initial TCORE, and physical performance-related variables are the best predictors of TCORE at fatigue or exhaustion. From a broader perspective, this systematic review provides relevant information for selecting appropriate methods in future studies designed to investigate exercise thermoregulation in rats.

Evaluation of anti-inflammatory, analgesic, and antipyretic activities of the ethanol extract from Murdannia loriformis (Hassk.) Rolla Rao et Kammathy.

Introduction: Murdannia loriformis (hassk) Rolla Roa et Kammathy, family Commelinaceae, is used by Chinese practitioners as a remedy for cancer in an early stage, and also for treating other diseases including colds, throat infections, pneumonia, diabetes mellitus, flu and inflammation. Although anticancer as well as other pharmacological effects of M. loriformis have been reported, its anti-inflammatory and other activities related to inflammation are still limited. Methods: The anti-inflammatory activity was evaluated using carrageenan- and arachidonic acid-induced paw edema in rats, and cotton pellet-induced granuloma formation in rats. The analgesic and antipyretic activities were determined by formalin test in mice and yeast-induced hyperthermia in rats, respectively. Results: The ethanol extract of the aerial part of M. loriformis exhibited anti-inflammatory activity on the rat paw edema induced by carrageenan and arachidonic acid. It also showed an inhibitory effect on the granuloma and the transudative formation of the rat implanted with cotton pellets as well as lowered the elevated serum alkaline phosphatase activity to normal level. It exerted potent analgesic effect on both the early and late phase of formalin test as well as the antipyretic effect on yeast-induced hyperthermic rats. The oral single high dose of the extract of 5,000 mg/Kg did not produce death or any abnormalities or changes of the internal organs of rats during 14 days of the observed period. Conclusion: The results obtained from this study support the use of the plant in traditional medicine for inflammatory ailments.

Phytochemical constituents and antipyretic activities of methanol leaf extract of &lt;i&gt;Costus afer&lt;/i&gt; (Family: Zingiberaceae)

The methanol extract of Costus afer leaf (MECAL) was evaluated for its antipyretic potential on normal body temperature and Brewer’s yeast induced pyrexia in albino rats model. Preliminary phytochemical analysis and acute toxicity test of the extract in mice was done. The result showed that the plant has good antipyretic effect. Yeast suspension (10 ml/kg body weight) elevated rectal temperature after 19 h of subcutaneous injection. Intraperitoneal administration of MECAL at 100, 200 and 300 mg/kg body weight showed significant reduction in normal rectal body temperature (35.96 ± 1.40, 35.38 ± 0.13 and 35.40 ± 0.60 respectively). MECAL at doses of 100, 200 and 300 mg/kg caused significant reduction of rectal temperature of hyperthermic rats by 37.75 ± 0.21, 38.10 ± 0.15 and 37.10 ± 0.32 respectively, in a dose-dependent manner after 5 h of treatment and the effect was comparable to that of the standard antipyretic drug-paracetamol (150 mg/kg body weight). The phytochemical analysis revealed the presence of alkaloids, carbohydrates, reducing sugars, flavonoids, tannins, saponins and glycosides. The LD50 using the methanol leaf extract of Costus afer was administered through intraperitoneal route in mice and was not toxic since no death was recorded at the dose of 5000 mg/kg. The study revealed that the methanol extract of Costus afer exhibited significant (P Keywords : Costus afer, anti-pyretic, Zingiberaceae, rats, phytochemistry Journal of Pharmaceutical and Allied Sciences , Vol. 7 No.3 (2010)

Systemic Hyperthermia Masks the Neuroprotective Effects of MK-801, but not Rosiglitazone in Brain Ischaemia

The use of neuroprotective agents has been under investigation for the treatment of ischaemic brain stroke. In this study, we examined the effects of rosiglitazone and MK-801, two potential neuroprotectants, on thromboembloic focal stroke in hyperthermic rats. The animals were assigned into groups of rosiglitazone, MK-801 and control, all under both normothermic and hyperthermic conditions. A focal ischaemia was induced by injection of preformed clot into the origin of the middle cerebral artery. The animals were assessed by measuring infarct size and brain oedema and also evaluating neurological deficit and seizure activity. Rosiglitazone improved infarct volume and neurological deficit in both normo- (36%) and hyperthermic (63%) animals; but MK-801 only improved normothermic animals. Our results do not support the use of MK-801 in hyperthermic conditions of brain stroke but suggest that rosiglitazone may preserve its efficiency even in hyperthermia.

Effects of induced hyperthermia on pharmacokinetics of ropivacaine in rats

Ropivacaine is a local anaesthetic used for epidural anaesthesia and postoperative pain relief. Hyperthermia is a very common sign of infection associated with variations in physiological parameters, which may influence drugs pharmacokinetics. The aim of this study was to determine the effects of induced hyperthermia on ropivacaine pharmacokinetics in rats. Two groups of six rats were given a single subcutaneous ropivacaine injection. Hyperthermia-induced animals were placed in a water bath to obtain a stable mean core temperature of 39.7 degrees C. After blood samples collection, ropivacaine serum concentrations and pharmacokinetic parameters were determined. Two other groups of six rats were sacrificed 30 min after ropivacaine injection to determine serum and tissues (brain and heart) concentrations. Our results (median +/- inter quartile range) reveal a significant increase of the total apparent clearance (0.0151 +/- 0.000800 L/min vs. 0.0134 +/- 0.00134 L/min), apparent volume of distribution (V(d)) (2.19 +/- 0.27 L vs. 1.57 +/- 0.73 L) and a significant decrease in exposure (488 +/- 50.6 mgxmin/L vs. 572 +/- 110 mgxmin/L) in induced-hyperthermia group. We observed a significant increase in brain ropivacaine concentration in hyperthermic rats (8.39 +/- 8.42 microg/g vs. 3.48 +/- 3.26 microg/g) and no significant difference between cardiac concentrations in the two groups (5.38 +/- 4.83 microg/g vs. 3.73 +/- 2.44 microg/g). Results suggest a higher tissular distribution of ropivacaine and an increase in blood-brain barrier permeability during hyperthermia. The hyperthermia-induced increase in V(d) could be responsible for an increase in cerebral ropivacaine toxicity. These experimental data provide a basis for future clinical investigations in relation to local anaesthetic use in hyperthermic patients.

Post-cardiac arrest temperature manipulation alters early EEG bursting in rats

Hypothermia improves outcomes after cardiac arrest (CA), while hyperthermia worsens injury. EEG recovers through periodic bursting from isoelectricity after CA, the duration of which is associated with outcome in normothermia. We quantified burst frequency to study the effect of temperature on early EEG recovery after CA. Twenty-four rats were divided into three groups, based on 6h of hypothermia (T=33 degrees C), normothermia (T=37 degrees C), or hyperthermia (T=39 degrees C) immediately post-resuscitation from 7-min asphyxial CA. Temperature was maintained using surface cooling and re-warming. Neurological recovery was defined by 72-h neurological deficit score (NDS). Burst frequency was higher during the first 90min in rats treated with hypothermia (25.6+/-12.2min(-1)) and hyperthermia (22.6+/-8.3min(-1)) compared to normothermia (16.9+/-8.5min(-1)) (p<0.001). Burst frequency correlated strongly with 72-h NDS in normothermic rats (p<0.05) but not in hypothermic or hyperthermic rats. The 72-h NDS of the hypothermia group (74, 61-74; median, 25-75th percentile) was significantly higher than the normothermia (49, 47-61) and hyperthermia (43, 0-50) groups (p<0.001). In normothermic rats resuscitated from CA, early EEG burst frequency is strongly associated with neurological recovery. Increased bursting followed by earlier restitution of continuous EEG activity with hypothermia may represent enhanced recovery, while heightened metabolic rate and worsening secondary injury is likely in the hyperthermia group. These factors may confound use of early burst frequency for outcome prediction.

On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats

The mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonergic (5-HT) toxicity remain unclear. It has been suggested that MDMA depletes 5-HT by increasing brain tyrosine levels, which via non-enzymatic hydroxylation leads to DA-derived free radical formation. Because this hypothesis assumes the pre-existence of hydroxyl radicals, we hypothesized that MDMA metabolism into pro-oxidant compounds is the limiting step in this process. Acute hyperthermia, plasma tyrosine levels and concentrations of MDMA and its main metabolites were higher after a toxic (15 mg/kg i.p.) vs. a non-toxic dose of MDMA (7.5 mg/kg i.p.). The administration of a non-toxic dose of MDMA in combination with l-tyrosine (0.2 mmol/kg i.p.) produced a similar increase in serum tyrosine levels to those found after a toxic dose of MDMA; however, brain 5-HT content remained unchanged. The non-toxic dose of MDMA combined with a high dose of tyrosine (0.5 mmol/kg i.p.), caused long-term 5-HT depletions in rats treated at 21.5 °C but not in those treated at 15 °C, conditions known to decrease MDMA metabolism. Furthermore, striatal perfusion of MDMA (100 μM for 5 h) combined with tyrosine (0.5 mmol/kg i.p.) in hyperthermic rats did not cause 5-HT depletions. By contrast, rats treated with the non-toxic dose of MDMA under heating conditions or combined with entacapone or acivicin, which interfere with MDMA metabolism or increase brain MDMA metabolite availability respectively, showed significant reductions of brain 5-HT content. Altogether, these data indicate that although tyrosine may contribute to MDMA-induced toxicity, MDMA metabolism appears to be the limiting step.

Anti-inflammatory, analgesic and antipyretic activities of the extract of gamboge from Garcinia hanburyi Hook f.

In Thai floklore medicine, gamboge, the yellow gum-resin secreted from Garcinia hanburyi, is used for infected wound, pain and edema The ethyl acetate extract from Garcinia hanburyi (GH5763) was assessed for anti-inflammatory, analgesic and antipyretic activities using experimental animal models. It was found that GH5763 possessed inhibitory activity on acute phase of inflammation as seen in ethyl phenylpropiolate-induced ear edema and carrageenin-induced hind paw edema in rats. However, GH5763 did not elicit any inhibitory effect on arachidonic acid-induced hind paw edema. In subchronic inflammatory model, GH5763 provoked a significant reduction of both transudative and proliferative phase when tested on cotton pellet-induced granuloma model. GH5763 also reduced the alkaline phosphatase activity in serum of rats in this animal model. In the analgesic test, GH5763 elicited inhibitory activity on acetic acid-induced writhing response and on both the early and the late phase of formalin test. Moreover, GH5763 also possessed an excellent antipyretic effect when tested in yeast-induced hyperthermic rats. It is postulated that the anti-inflammatory, analgesic and antipyretic activities of GH5763 are caused by the inhibition of the prostaglandin biosynthesis.

Prolonged Febrile Seizures and Temporal Lobe Epilepsy

The presence of spontaneous limbic seizures using chronic video monitoring with concurrent hippocampal and cortical EEGs, in adult rats (starting at 3 months of age) that had sustained experimental febrile seizures (FS) on postnatal day 10 was compared to hyperthermic control rats whose FS had been controlled, in a study at University of California, Irvine, CA, and University of Pennsylvania, Philadelphia.

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

Encephalopathy, brain edema and intracranial hypertension are neurological complications responsible for substantial morbidity/mortality in patients with acute liver failure (ALF), where, aside from liver transplantation, there is currently a paucity of effective therapies. Mirroring its cerebro-protective effects in other clinical conditions, the induction of mild hypothermia may provide a potential therapeutic approach to the management of ALF. A solid mechanistic rationale for the use of mild hypothermia is provided by clinical and experimental studies showing its beneficial effects in relation to many of the key factors that determine the development of brain edema and intracranial hypertension in ALF, namely the delivery of ammonia to the brain, the disturbances of brain organic osmolytes and brain extracellular amino acids, cerebro-vascular haemodynamics, brain glucose metabolism, inflammation, subclinical seizure activity and alterations of gene expression. Initial uncontrolled clinical studies of mild hypothermia in patients with ALF suggest that it is an effective, feasible and safe approach. Randomized controlled clinical trials are now needed to adequately assess its efficacy, safety, clinical impact on global outcomes and to provide the guidelines for its use in ALF.

Hyperthermia Masks the Neuroprotective Effects of Tissue Plaminogen Activator

Previously, we have shown that hyperthermia significantly increased neuronal damage after ischemic injury in a focal embolic model of stroke in rats. In the present study, we examined the effects of hyperthermia on the efficacy of thrombolytic therapy in this stroke model. In part A, efficacy of tissue plaminogen activator (tPA) treatment was examined in normothermic and hyperthermic rats after embolization of preformed clots into middle cerebral artery (MCA). In part B, brain perfusion deficits were assessed in rats after MCA occlusion. In part C, blood-brain barrier (BBB) permeability was examined in rats after MCA occlusion. In part D, we examined the influence of hyperthermia on fibrinolytic activity of tPA in vitro. Results showed that treatment with tPA significantly reduced infarct volume in normothermic and 38 degrees C hyperthermic rats. When compared with normothermic rats, perfusion deficits in hyperthermic rats were significantly increased at both 3 hours and 6 hours after ischemic injury. Compared with normothermic sham-operated rats, Evans blue dye extravasation was increased in the injured rats with 39 degrees C hyperthermia. In vitro study showed that hyperthermia increased the fibrinolytic activity of tPA. The present study shows that hyperthermia masks the neuroprotective effects of tPA treatment after ischemic injury and that this may be caused by increased BBB permeability, increased edema, and early progression of ischemic penumbral region to irreversibly damaged tissue as shown by progressively increasing perfusion deficits in hyperthermic rats.

Heart rate variability as an index of physiological strain in hyperthermic and dehydrated rats

Telemetry-equipped rats were subjected to hyperthermia (H, T c=41.5°C) with and without dehydration (D, 9% loss of body weight) stresses. Time domain and spectral analysis of heart rate variability indicated that the dehydrated hyperthermic (DH) rats had increased sympathetic activity compared to H rats, and DH rats had decreased parasympathetic activity compared to less hyperthermic D rats. These non-invasive measures of physiological strain discriminated the more physiologically stressful of these states.

Anti-inflammatory and antipyretic properties of Clerodendrum petasites S. Moore

The methanol extract from Clerodendrum petasites S. Moore (CP extract) was assessed for anti-inflammatory and antipyretic activities on the experimental animal models. It was found that CP extract possessed moderate inhibitory activity on acute phase of inflammation in a dose-related manner as seen in ethyl phenylpropiolate-induced ear edema (ED 50=2.34 mg/ear) as well as carrageenin-induced hind paw edema (ED 30=420.41 mg/kg) in rats. However, CP extract did not elicit any inhibitory effect on arachidonic acid-induced hind paw edema in rats. In subchronic inflammatory model, CP extract provoked a significant reduction of transudation but had no effect on proliferative phase when tested in cotton pellet-induced granuloma model. CP extract also reduced the alkaline phosphatase activity in serum of rats in this animal model. Moreover, CP extract possessed an excellent antipyretic effect when tested in yeast-induced hyperthermic rats. It is postulated that the anti-inflammatory and antipyretic effects of CP extract are caused by the inhibition of the prostaglandin synthesis. Anyhow, CP extract did not possess any analgesic activity in acetic acid-induced writhing response in mice. The results obtained show that C. petasites has beneficial properties since it possesses potent antipyretic and moderate anti-inflammatory activities without ulcerogenic effect.

Thermal control of mother–young contact revisited: Hyperthermic rats nurse normally

Morphine (MOR) is known to inhibit maternal behavior and induce hyperthermia; at appropriate doses, concurrent administration of naloxone (NAL) counteracts its disruption of maternal behavior but not the hyperthermia. We used these findings to evaluate the view that lactating rats terminate nursing due to intolerable hyperthermia. After a dam–litter separation of 4 h on Day 7 postpartum (PP), mother–litter interactions were observed continuously for 1 h. One hour before reunion, the dams received two injections (1 ml/kg ip each) of saline (SAL), MOR (20 mg/kg) and/or NAL (1 mg/kg) in the following combinations ( n=7 each): SAL+SAL, SAL+NAL, MOR+SAL or MOR+NAL. MOR profoundly disrupted maternal behavior, thereby preventing litter weight gains; these effects were completely counteracted by NAL, which alone had no discernible effects. In contrast, MOR-induced hyperthermia (∼0.7 °C increase in each hour, before and after reunion with pups) was not antagonized by NAL at the doses used. Thus, an additional 0.7–1.4 °C of body temperature (T) did not delay the onset or reduce the duration of nursing compared with SAL-treated controls. Further, there were no group differences in behaviors displayed both shortly before and after a nursing bout that included milk ejections or in the resumption of nursing. Together with earlier methodological and empirical criticisms of the thermal control theory, as well as knowledge about the somatosensory determinants of nursing, the present results suggest that nursing bouts in lactating rats are not limited by the mother's T.

Hyperthermic stress affects the thermal modulation of glucocorticoid–receptor affinity

In vitro binding of a steroid hormone (triamcinolone acetonide) to hepatic glucocorticoid receptors was studied in liver cytosols prepared from untreated control rats and rats sacrificed after being exposed in vivo to whole body hyperthermia (41 or 42°C). Positive temperature modulation of glucocorticoid–receptor affinity (decrease of affinity with increasing temperature) was well expressed in all preparations. In preparations from hyperthermic rats, alterations of a possible functional (adaptive) significance have been recorded: the amplitude of positive thermal modulation was reduced, and its lower-temperature limit shifted towards higher temperatures.

TREATMENT OF HYPERTHERMIA-INDUCED EXTRAVASATION WITH HYPERTONIC SALINE (7.5%) IN 6% DEXTRAN 70 (HSD) IN WISTAR/FURTH RATS

This study determined the effectiveness of hypertonic saline (7.5%) in 6% Dextran 70 (HSD) in reducing hyperthermia-induced extravasation in Wistar/Furth (WF) rats and compared this extravasation with that previously reported in Sprague-Dawley (SD) rats. Wistar/Furth rats (male, n = 12/group, 300-325 g) were placed unrestrained in a chamber (41.5 degrees C) until a core temperature (Tc) of 42.6 degrees C was attained. Immediately following heat exposure, HSD or normal saline (4 mL/kg) was administered via jugular catheter, followed 15 min later by Evan's blue (Eb, 25 mg/kg) in normal saline. After another 15-min interval, animals were anesthetized, exsanguinated, tissues removed and washed in normal saline, and Eb was extracted with formamide. Another group of normothermic WF rats were also given Eb and had tissues harvested. Comparisons were made to extravasation in normothermic and hyperthermic SD rats. In hyperthermic SD rats, Eb content increased significantly in liver, kidney, and intestinal tissues. In hyperthermic WF rats compared to normothermic WF rats, Eb content of kidney and spleen was increased; however, Eb content of heart, skeletal muscle, and intestine was significantly decreased. HSD-treated WF rats had increased extravasation in intestinal tissue compared to that of saline-treated rats. However, HSD treatment resulted in significant decreases in wet weight/dry weight ratios of heart (4.34 +/- 0.10 versus 4.51 +/- 0.11) and skeletal muscle tissue (3.78 +/- 0.08 versus 3.91 +/- 0.08). Findings of this study indicate that HSD did not prevent the hyperthermia-induced extravasation of Eb in kidney and spleen; that the increase in plasma volume following HSD administration is most likely due to the movement of fluid into the vasculature from the skeletal muscle mass; and that the WF strain may have limited value for the study of extravasation.

Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats.

Previous work has established that there is an increase in endothelial permeability in hyperthermic rats. This work assessed the potential of the calcium channel blocker (E)-1-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine) as a pretreatment to ameliorate this extravasation. Five groups of male rats (n=12 rats per group, 400-500 g) were given 0, 0.3, 1, 2, or 3 mg/kg flunarizine (FL0, FL0.3, FL1, FL2, and FL3, respectively) by gavage 30 min prior to induction of hyperthermia. Hyperthermia was achieved by placing unrestrained animals in their own cages in a chamber maintained at 41.5 degrees C until a core temperature (Tc) of 42.6 degrees C was attained. Then, 25 mg/kg of Evans blue in saline was administered via a jugular cannula. After 15 min the animals were anesthetized, exsanguinated, tissues removed and washed in saline, and Evans blue extracted with formamide. As the dose of flunarizine was increased, there was a significant (P<0.05) reduction of Evans blue recovered from the liver, kidney, lung, spleen, and intestinal tissue. Endurance time in the heat to reach a Tc of 42.6 degrees C increased significantly from 194+/-39 min (mean+/-SD) with FL0 to 275+/-33 min with FL1, but decreased again with FL2 (206+/-42) and FL3 (199+/-60). Thus, flunarizine pretreatment attenuated hyperthermia-induced extravasation, and 1 mg/kg flunarizine markedly increased the tolerance time to heat exposure.

Hyperthermia-induced changes in the vascular permeability of rats: a model system to examine therapeutic interventions

Extravasation in the heart, liver, lung, kidney, spleen, gastrocnemius, and duodenum was quantified in normothermic and hyperthermic (core temperature ( T c)=41.5, 42, or 42.6°C) rats. Following attainment of the target T c, Evans blue (Eb) was administered via jugular cannula; the animals were anesthetized, exsanguinated, tissues removed and washed in saline, and Eb extracted with formamide. There was significantly ( p<0.05) more Eb (μg/g of dry wt of tissue, mean±SD) in the tissues of severely hyperthermic ( T c=42.6°C) rats vs that of control rats: liver — 198±39 vs 125±28, kidney — 376±68 vs 176±60, and small intestine — 170±49 vs 106±20. This model may be useful in evaluating the efficacy of treatment modalities designed to sustain vascular integrity in the face of environmental insult.

Brain temperature modifies glutamate neurotoxicity in vivo.

The purpose of this study was to examine the effects of mild hypothermia and hyperthermia on glutamate excitotoxicity. Glutamate-induced cortical lesions were produced in hypothermic (32 degrees C), normothermic (37 degrees C), and hyperthermic (40 degrees C) rats by perfusion of a 0.5 M glutamate solution via a microdialysis probe. The volume of the lesion 7 days after glutamate perfusion was quantified histologically by image analysis. This histological assessment was performed in two experiments; in one, each of the target temperatures was induced before glutamate perfusion, and in the other, each of the target temperatures was induced after stopping the glutamate perfusion. We also examined the effect of temperature on the diffusion of exogenously delivered material in the extracellular space using autoradiography of the perfused glutamate solution containing 14C-labeled sucrose. In the two experiments in which each of the target temperatures was induced before or after glutamate perfusion, the volume of damage was reduced by mild hypothermia and enlarged by mild hyperthermia. The volume of 14C diffusion also increased as brain temperature increased. These results provide evidence that small variations of brain temperature modify glutamate excitotoxicity. The results also suggest that the change in glutamate diffusion in the extracellular space is one mechanism by which mild hypothermia and hyperthermia exert their protective and harmful effects respectively.