Cerebral Water Content Research Articles

Stereoscopic study on capillary density of early brain oedema in a dog postburn model

Background After severe burn, the effective circulating blood volume decreases drastically due to massive body fluid loss, and blood redistribution occurs to maintain sufficient blood supply to vital organs. Blood perfusion of brain tissue changes and the permeability of the blood brain barrier increases due to ischaemia and hypoxia, which results in brain oedema. The goal of this study was to explore the changes of cerebral blood flow during the brain oedema at the early stage of severe burn. Methods Twenty-six dogs were randomly divided into control and 6, 12, 18, and 24 PBH groups. The manifestation of MRI and histopathology, changes of brain water content were investigated; the shapes and distribution of the cerebral capillaries were observed with the endogenous AKP histochemical staining method and image analysis technique. The volume, surface, and length fractions of cerebral capillaries were tested and analysed with a stereographic method in each group, respectively. Results The earliest changes of cerebral oedema were found at 12 PBH with MRI, which showed the brain swelling as characteristic of cerebral morphological changes. The decrease of SIR on T 1WI was not observed until it was above 10%. Signal of T 2WI increased for 8.29% at 24 PBH. Histological changes were observed as early as 6 h after burn, accompanied by swelling of endothelial cells and peri-vascular astrocytes, vacuolation took place in neurons at 12 h after burn, necrosis of different degrees in capillary endothelium, neurons, and axons. Increase in cerebral water content was noted at 6 h postburn, and it was the most marked in 24 postburn group.The distributional density of capillaries became thicker at 6 h and 12 h postburn, the shapes were normal. The capillaries became sparser at 18 h, and almost disappeared from view, only a few ends of capillaries in the shape of vine were seen at 24 h postburn. The percentages of capillary volume, surface, and length fractions were increased at 6 h and 12 h, but decreased at 18 h and reached the lowest point at 24 h postburn ( P < 0.05). Conclusion We suggest that the changes of cerebral blood flow might play an important role in the pathogenesis of brain oedema in the early stage of severe burn.

Cerebrovascular response to continuous cold perfusion and hypothermic circulatory arrest

Clinical and laboratory studies have documented changes in cerebrovascular resistance after hypothermic circulatory arrest, both with and without adjunctive cerebral perfusion modalities. This study was designed to clarify whether these changes are due to cerebral edema, resistance vessel abnormalities, or alterations in the cerebral microcirculation. Four mature swine underwent hypothermic circulatory arrest for 60 minutes, and 7 mature swine underwent cold cerebral perfusion for 60 minutes to simulate antegrade selective perfusion. All were rewarmed and weaned from cardiopulmonary bypass. Pial vascular diameter and reactivity were measured in vivo through a cranial window and ex vivo in an organ chamber; cerebral microvascular endothelium was studied in culture for release of vasoactive mediators. Cerebral water content was recorded. Cold perfusion caused pial arteriole and venule constriction, whereas hypothermic circulatory arrest alone caused pial arteriole and venule dilatation. Cold perfusion caused a temporal loss of endothelium-dependent vasodilatation, most notably to bradykinin. Hypothermic circulatory arrest caused a loss of nitric oxide-mediated endothelium-dependent vasodilatation. Endothelium-independent vasoreactivity remained intact in both groups. Endothelial cells from the cold group had a vasoconstrictive secretory phenotype, whereas endothelial cells from the hypothermic circulatory arrest group had a vasodilatory phenotype. Cerebral water content was the same in both groups. The increase in cerebrovascular resistance observed after cold cerebral perfusion is caused by resistance vessel constriction and may be promoted by an altered microcirculation. Hypothermic circulatory arrest alone is associated with endothelium-dependent vasoparesis. Both could contribute to cerebral injury in the early hours after operation.

Role of Vasopressin V1a and V2 Receptors for the Development of Secondary Brain Damage after Traumatic Brain Injury in Mice

Brain edema is still one of the most deleterious sequels of traumatic brain injury (TBI), and its pathophysiology is not sufficiently understood. The goal of the current study was to investigate the role of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), an important regulator of tissue water homeostasis, for the formation of post-traumatic brain edema, intracranial pressure (ICP), brain damage, and functional deficits following brain trauma. C57/B16 mice (n=112) were subjected to controlled cortical impact (CCI; 8m/s, 1 mm). At 3 min after trauma, animals received 500 ng of the AVP V(1a)-receptor antogonist (deamino-Pen(1), O-Me-Tyr(2), Arg(8)]-Vasopressin) or 500 ng of the AVP V2-receptor antagonist (adamantaneacetyl(1), O-Et-D-Tyr(2),Val(4), Abu(6),Arg(8,9)]-Vasopressin) by intracerebroventricular injection. After trauma, cerebral water content (24 h), ICP (24 h), contusion volume (24 h and 7 days), and functional outcome (1-7 days) were assessed (n=8 per experimental group). Post-traumatic inhibition of AVP V(1A) receptors reduced ICP by 29% (p < 0.05), brain water content by 45% (p < 0.05), and secondary contusion expansion by 37% (p < 0.05), and it significantly improved motor function 6 and 7 days after trauma (p < 0.05). Inhibition of AVP V2 receptors had no significant effect. The current results demonstrate that vasopressin V(1A) receptors are involved in the pathogenesis of brain edema formation and the subsequent development of secondary brain damage after traumatic brain injury. Accordingly, our study suggests that vasopressin V(1A) receptors may represent a novel therapeutic target for the treatment of post-traumatic brain edema and secondary brain damage.

Fast quantitative mapping of absolute water content with full brain coverage

Quantitative mapping of water content, especially in the human brain, has the potential to provide important information for the study and diagnosis of diseases associated with a focal or global change in tissue water homeostasis. In the current work, an imaging method for the precise and accurate quantification of tissue water content is presented. The method allows the acquisition of water content maps with voxel dimensions of 1×1×2 mm3 and full brain coverage in less than 10 min on a standard clinical 1.5 T scanner. The precision was optimised for human brain imaging and possible sources of systematic error were carefully investigated, demonstrating the ability of the method to quantify water content with high accuracy and precision. The approach was validated in phantom experiments and quantitative cerebral water content maps of a group of 10 healthy volunteers were obtained.

Quantitative cerebral water content mapping in hepatic encephalopathy

There is increasing evidence that the pathophysiology of hepatic encephalopathy is tightly associated with low-grade cerebral oedema; however, no method has yet specifically and unambiguously confirmed this hypothesis in vivo. The current study describes the quantitative measurement of localised water content using MRI in a cohort of 38 patients suffering from hepatic encephalopathy. A significant global increase in cerebral water content was observed in white matter whereas water content in grey matter was globally unaffected. However, significant spatial variations in the water content distribution, especially in grey matter, were observed and were correlated with disease grade and critical flicker frequency. In addition, regions-of-interest were defined and a significant change in water content with disease grade was found in the frontal and occipital white matter, the globus pallidus, the anterior limb of the internal capsule and the putamen. No association of water content and HE grade was established for the occipital visual and frontal cortices, the thalamus, the posterior limb of the internal capsule, the caudate nucleus and the coronal white matter. In conclusion, the measurements presented here are the first direct and quantitative demonstration of the presence of low-grade cerebral oedema in patients with hepatic encephalopathy. Further, absolute changes in tissue water content were quantified for various brain regions.

Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy

Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mice's heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT.For more information on this article, see medicalphysicsweb.org

Emboli Formation Rather Than Inflammatory Mediators Are Responsible for Increased Cerebral Water Content After Conventional and Assisted Beating-Heart Myocardial Revascularization in a Porcine Model

Emboli and proinflammatory mediators are suspected of generating cerebral edema after coronary surgery. In contrast to cardiopulmonary bypass (CPB), off-pump coronary artery bypass surgery (OPCAB) reduces microemboli count and proinflammatory mediator release but carries the risk of hemodynamic instability. A microaxial blood pump can augment cardiac output. Coronary bypasses were constructed in pigs with CPB and cardioplegia (n=9), OPCAB (n=9), or blood-pump support CAB (n=9). Nine animals underwent sham operation. Embolus count was monitored and regional cerebral blood flow was assessed with microspheres in 21 brain specimens per animal (n=189 per group). Interleukins 6 and 8 and tumor necrosis factor-alpha concentrations were determined. These variables were studied before, during, and for 4 hours after surgery. Finally, cerebral water content was determined. During CPB and blood-pump CAB, a significant number of emboli were counted in contrast to OPCAB and controls (P<0.05). During CPB, regional cerebral blood flow was affected (32 of 189) and showed reactive hyperemia except in 10 specimens after aortic cross-clamp release. This impairment persisted in 20 specimens. During and after OPCAB, regional cerebral blood flow remained nearly unchanged but showed low flow during (58 of 189) and after (35 of 189) the blood-pump run. A significant increase in proinflammatory mediators was observed only in the CPB group. CPB and blood-pump CAB significantly increased cerebral water content (P<0.05). A strong correlation between embolic load and cerebral water content was observed in all groups. No correlation between proinflammatory mediator release and cerebral water content was detected. Emboli formation rather than inflammatory mediators are responsible for increased cerebral water content after conventional and assisted beating-heart myocardial revascularization.

Effect of hemoglobin vesicle, a cellular-type artificial oxygen carrier, on middle cerebral artery occlusion- and arachidonic acid-induced stroke models in rats

Hemoglobin vesicle (HbV), which is also called liposome-encapsulated hemoglobin, functions as a hemoglobin-based oxygen carrier and is expected to be utilized in emergency situations including hemorrhagic shock and several kinds of ischemic diseases. In the present study, we evaluated the efficacy of HbV for improving stroke-related symptoms induced by middle cerebral artery (MCA) occlusion/reperfusion and an intra-internal carotid arterial injection of arachidonic acid (AA) in rats. When HbV (10 mL/kg, i.v.) was administered to rats immediately after the MCA occlusion, it reduced the cerebral infarct volumes of the cortex and total of the cortex plus sub-cortex significantly as compared with saline as a vehicle. In AA-induced stroke model, HbV (10 mL/kg, i.v.) improved the motor dysfunction score and inhibited the increase in cerebral water content suggesting it could suppress cerebral edema. These results strongly suggest that HbV would provide a novel beneficial option for the treatment of stroke, especially acute ischemic stroke.

Do sodium channel blockers have neuroprotective effect after onset of ischemic insult?

Objective: Cerebral ischemia causes a series of pathophysiologic events that may result in cerebral infarct. Some neurons are more vulnerable to ischemia, particularly pyramidal neurons in the hippocampal CA1 region. Pharmacologic intervention for treatment of cerebral ischemia aims to counteract secondary neurotoxic events or to interrupt the progression of this process. In the present study, we compare the neuroprotective effects of sodium channel blockers (mexiletine, riluzole and phenytoin) and investigate whether they have neuroprotective effect when given after ischemic insult.Methods: A transient global cerebral ischemia model was performed in this study by clipping bilateral common carotid arteries during 45 minutes. Riluzole (8 mg/kg), mexiletine (80 mg/kg) and phenytoin (200 mg/kg) were injected into the rats intraperitoneally 30 minutes before or after reperfusion. Lipid peroxidation levels and cerebral water contents were evaluated 24 hours after ischemia. Histopathologic assessment of hippocampal region was determined 7 days after ischemia.Results: Riluzole, mexiletine and phenytoin treatment after global ischemia significantly decreased water content of the ischemic brain (p<0.05 for each). No significant difference was observed in cerebral edema among the drug treatment groups (p>0.05). When pre-treatment and post-treatment groups were compared with each other, only riluzole pre-treatment group revealed better result for cerebral edema (p<0.05). Pre-treatment with these drugs revealed significantly better results for the malonyldialdehyde (MDA) level and the number of survival neuron on the hippocampal region than the post-treatment groups.Conclusion: It is demonstrated that riluzole, mexiletine and phenytoin are potent neuroprotective agents in the rat model of transient global cerebral ischemia, but they are more effective when given before onset of the ischemia.

Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice

Inflammatory reaction plays an important role in cerebral ischemia-reperfusion injury, however, its mechanism is still unclear. Our study aims to explore the function of Toll-like receptor 4 (TLR4) in the process of cerebral ischemia-reperfusion. We made middle cerebral artery ischemia-reperfusion model in mice with line embolism method. Compared with C3H/OuJ mice, scores of cerebral water content, cerebral infarct size and neurologic impairment in C3H/Hej mice were obviously lower after 6 h ischemia and 24 h reperfusion. Light microscopic and electron microscopic results showed that cerebral ischemia-reperfusion injury in C3H/Hej mice was less serious than that in C3H/OuJ mice. TNF-α and IL-6 contents in C3H/HeJ mice were obviously lower than that in C3H/OuJ mice with ELISA. The results showed that TLR4 participates in the process of cerebral ischemia-reperfusion injury probably through decrease of inflammatory cytokines. TLR4 may become a new target for prevention of cerebral ischemia-reperfusion injury. Our study suggests that TLR4 is one of the mechanisms of cerebral ischemia-reperfusion injury besides its important role in innate immunity.

Gray matter abnormalities in autism spectrum disorder revealed by T2 relaxation

To perform quantitative T2 relaxation measurements to evaluate cerebral water content in children with autism. Sixty 2- to 4-year-old children with autism spectrum disorder (ASD), 16 age-matched children with idiopathic developmental delay (DD), and 10 children with typical development (TD) were scanned on a 1.5 T GE MRI scanner to obtain dual-echo fast spin echo images (2.5 mm thick, 0-mm gap). Images were segmented into gray and white matter and used to mask regions of interest for calculating T2 for each tissue type. Analysis of variance, covarying for age and sex, was used to compare T2 between groups, and correlations were used to compare T2 to IQ measures. Children with ASD had prolonged cortical gray matter T2, but white matter T2 was not significantly different, compared with the children with TD. T2 was prolonged in cortical gray matter and white matter in children with DD compared with children with ASD or TD. Significant interactions between T2 measures and IQ were not observed. Prolonged gray and white matter T2 in the children with developmental delay likely represents a delay in neuronal development and maturation. Prolonged T2 in gray matter, but not white matter, observed in children with autism spectrum disorder may signify abnormal developmental processes specific to autism.

Chronic daily administration of ethyl docosahexaenoate protects against gerbil brain ischemic damage through reduction of arachidonic acid liberation and accumulation

Recently, we reported that dietary ethyl docosahexaenoate (Et-DHA) intake decreases the level of membrane arachidonic acid (AA), which reduces the generation of AA metabolites in ischemic gerbil brain. As an extended study, we further investigated the influence of the chronic administration of Et-DHA on free AA levels after ischemia. In addition, Na,K-ATPase activity, cation content, cerebral edema and brain damage were also evaluated. Weanling male gerbils were orally pretreated with either Et-DHA (200 mg/kg) or vehicle, once a day for 10 weeks, and subjected to transient forebrain ischemia by bilateral common carotid occlusion for 30 min. Time-course analyses revealed that pretreatment with Et-DHA, compared with pretreatment with the vehicle, significantly decreased the brain's free AA levels during ischemia (5, 15 and 30 min) and after reperfusion (5, 10, 15 and 30 min), and attenuated the decline of Na,K-ATPase activity at examined time points. Pretreatment with Et-DHA significantly prevented an increase in Na + concentration and a decrease in K + concentration after 24 h of reperfusion, which resulted in lower cerebral water content. Reduced brain infarct volume and low animal mortality were also observed in Et-DHA-treated animals. These data suggest that the reduction of ischemia-induced AA liberation and accumulation by Et-DHA pretreatment may be attributable to (a) protection against the decline of Na,K-ATPase activity, (b) postischemic cerebral edema and brain damage and (c) animal mortality.

Regional cerebral perfusion and brain water content after operative myocardial revascularisation in an adult porcine model: effect of cerebral emboli formations

Regional cerebral perfusion and brain water content after operative myocardial revascularisation in an adult porcine model: effect of cerebral emboli formations

Fully-automated detection of cerebral water content changes: Study of age- and gender-related H 2O patterns with quantitative MRI

We present a simple and robust method for the automated image analysis of quantitative cerebral water content maps acquired with MRI. The method is based on a new approach for the absolute and quantitative mapping of water content in vivo. Water content maps were automatically segmented into grey and white matter by employing the quantitative T 1 information acquired as part of the water content mapping procedure. Based on the segmented maps, twenty-two parameters sensitive to both absolute water content and its spatial organisation are automatically extracted without user interaction. The parameters include, amongst others, absolute water content in grey and white matter and spatial asymmetries of the cerebral water content distribution. Significant age- and gender-related changes in the parameters determined were observed in a study of forty-four healthy subjects. Most notably, the grey matter water content decreases at a rate of 0.034%/year for females between the 3rd and 8th decade of life, whilst a much stronger decrease is observed in males which sets in after the 5th decade of life. In addition, female grey matter water content is, on average, 1.2% higher than the respective male grey matter water content. In contrast to the heterogeneity observed in grey matter, no significant physiological variation was observed for white matter water content. In addition to absolute grey matter water content, characteristic age- and gender-specific variations were also observed in most of the other variables. To check the potential loss of information associated with the large reduction of the dimensionality of the dataset to 22 parameters only, the age and gender of each individual subject were predicted by employing robust linear discriminant analysis based on only the determined twenty-two variables. The median deviation between predicted and real age was 6.3 years resulting in a high correlation coefficient between both values ( r = 0.69). Gender is correctly predicted in 68.2% of all cases which improves to 87.5% when age-dependent effects are first corrected, demonstrating the high information content present in the variables even though the dimension of the dataset was significantly reduced. These results form the baseline for future studies of cerebral pathology. The method presented is fully automated, robust and flexible, making it an ideal tool for routine application in both neuroscientific studies and clinical diagnosis based on the quantitative measurement of cerebral water content.

The effect of cerebral emboli formations after conventional, off-pump and assisted beating heart myocardial revascularisation on regional cerebral perfusion and water content in an adult porcine model

The effect of cerebral emboli formations after conventional, off-pump and assisted beating heart myocardial revascularisation on regional cerebral perfusion and water content in an adult porcine model

Effects of Corydalis ambailis migo total alkaloids on experimental cerebral ischemia

To observe the protective effects of Corydalis ambailis migo total alkaloids (COAMTA) on cerebral ischemia/reperfusion injury in rats and to investigate its mechanism. The effects of COAMTA on decapitated gasping mouse model and rat model of middle cerebral artery ischemia (2 h)/reperfusion (22 h) were observed. The neurological scale, cerebral infarcted volume and cerebral water content subjected to cerebral middle artery ischemia/reperfusion in rats were recorded. The activities of nitric oxide synthase (NOS) and superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in the ratso brain were measured. Cell apoptosis in ischemic penumbral area was observed with light microscope in the method of terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL). The average gasping time of the mice (6.0 mg/kg or 9.0 mg/kg COAMTA) was significantly prolonged, the cerebral infarcted volume and cerebral water content of the rats (5.0 mg/kg or 7.5 mg/kg COAMTA) were significantly decreased, as compared with the control groups. The average activity of SOD in cerebral tissue of the rats (5.0 mg/kg or 7.5 mg/kg COAMTA) was significantly higher than that of the control groups, meanwhile, the average activity of NOS and the content of MDA declined significantly. The cell apoptosis in ischemic penumbral area of the rats (5.0 mg/kg COAMTA) was significantly inhibited as compared with the control groups. COAMTA can facilitate the protection against cerebral ischemia/reperfusion damage. The mechanism is related to inhibiting the activity of NOS and lipoperoxidation, increasing the activity of SOD and decreasing the neuronal apoptosis.

Cilostazol reduces brain lesion induced by focal cerebral ischemia in rats—an MRI study

To investigate the effects of cilostazol on the hemispheric ischemic lesion, we monitored the apparent diffusion coefficient (ADC) and T2 images by MRI techniques in comparison with histology at the terminal of and after 24-h reperfusion following 2-h occlusion of middle cerebral artery (MCA). The ADC values of tissue water and T2-weighted images were quantified by high field magnetic resonance. No significant difference was observed by ADC image among vehicle and cilostazol treatment groups when measured during MCA occlusion. Oral treatment with cilostazol 30 mg/kg two times at 5 min and 4 h significantly suppressed the hemispheric lesion area and volumes when detected by ADC, T2 images and histology, but 3 and 10 mg/kg cilostazol were without effect. Cilostazol (30 mg/kg) significantly reduced the increased cerebral water content at the ischemic hemisphere compared with vehicle group. In line with these results, the neurological deteriorations were much improved in the cilostazol-treated group. Taken together, it is concluded that post-treatment with cilostazol exerts a potent protective effect against cerebral infarct size by reducing the cytotoxic edema.

Administration of the soluble complement inhibitor, Crry-Ig, reduces inflammation and aquaporin 4 expression in lupus cerebritis

Changes in brain water and cerebral volume can lead to brain edema that may be one of the underlying causes of death in many neurological diseases. Cerebral water content is regulated by aquaporin 4 (AQ4) present in astrocytic end feet and around blood vessels. In systemic lupus erythematosus (SLE), magnetic resonance imaging (MRI) studies of the brain have demonstrated lesions with the prominent appearance of edema. Activation of complement may play a significant role in the pathogenesis of lupus cerebritis by causing inflammation that can lead to edema. In this study, the well-established MRL/lpr lupus mouse model was used to evaluate the role of complement in lupus cerebritis. IgG and C1q colocalized in perivascular deposits indicating that the blood–brain barrier was compromised. Both RNA and protein expressions of AQ4 were significantly increased in brains of MRL/lpr mice. Chronic administration of the soluble complement inhibitor, Crry-Ig, reduced inflammation as measured by decreased accumulation of IgG. In contrast to control MRL/lpr mice, AQ4 expression in complement inhibited MRL/lpr mice was not changed relative to untreated congenic controls. These results illustrate that complement activation in brains of lupus mice leads to enhanced AQ4 expression and inflammation. It is conceivable that increased AQ4 expression results in cerebral edema and hence complement inhibition may provide a new therapeutic option in inflammatory cerebral disorders such as lupus cerebritis.

Influence of aging on blood-brain barrier permeability and free radical formation following experimental brain cold injury.

The aim of this study is to investigate the effects of experimental cold brain injury on blood-brain barrier integrity, on brain oedema formation, and on lipid peroxidation and to compare the results between the aged and young rats. Cold brain injury was used to create a standard model of brain trauma in old and young rats. Disruption of the blood-brain barrier was analyzed by Evans blue method. The values of cerebral water content were calculated by using the fresh and dry weights of the cerebral hemispheres. Lipid peroxidation was assessed by measuring the tissue content of malonyl dialdehyde. Blood-brain barrier was destroyed significantly in young and old rats, but it was more severe in old rats. Accordingly, cerebral water content was increased in both groups, however this increase was significantly more prominent in old rats. No significant difference was found on malonyl dialdehyde levels between young and old rats. The blood-brain barrier was more easily disrupted in old rats, and this was supposed to be the basic event causing more secondary damage.

Effect of melatonin on cerebral edema in rats.

Melatonin (5-methoxy-N-acetyltrypamine), a chemical naturally produced in the pineal gland, has been suggested to be a free radical scavenger and an antioxidant. In the present study, the effect of melatonin on cold-induced brain edema was evaluated by determination of cerebral water content, blood-brain barrier permeability, and areas of infarct; the effects were also studied histopathologically. Brain edema was produced in rats by creating a lesion via cortical freezing. Animals were separated into four groups: sham-operated (craniectomy only); control (cold injury); sham-vehicle (cold injury plus saline); and melatonin treatment (cold injury plus melatonin). Melatonin was administered (50 mg/kg intraperitoneally) 15 minutes after the cold injury was induced. Twenty-four hours later, tissue samples from the core, from the periphery of the cold-injured hemisphere, and from the contralateral hemisphere symmetrical to the cold injury were obtained. Melatonin treatment reduced edema (mean +/- standard deviation; 86.22 +/- 1.54% in the control group versus 80.78 +/- 2.76% in the melatonin treatment group, P < 0.001) and blood-brain barrier permeability (45.34 +/- 2.75% in the control group versus 38.26 +/- 3.40% in the melatonin treatment group, P < 0.001) at the periphery of cold injury. Area of infarct reduced from 5.84 +/- 0.58% in the control group to 3.30 +/- 0.89% in the melatonin treatment group (P < 0.001). The effect of melatonin was also confirmed histopathologically. Melatonin was found to be neuroprotective in instances of cold-induced brain edema. Thus, melatonin may be a valuable therapeutic agent in the treatment of cerebral edema.