| Brain edema is the most familiar pathophysiologic event in neurosurgery and can be induced by brain trauma, brain tumors or cerebral ischemia. It occurs that the pathophysiologic changes in brain parenchyma and other organs result from brain edema. The development of edema is related to the damages of brain circulation, blood-brain barrier and neurons. Tumor necrosis factor-α, interleukins, nitric oxide (NO), free radicals and calcium overloading can influence the release of neurotansmitters, the signal transduction in neurons and the activation of protein kinase. The result is that brain edema and neurons apoptosis occur. According to the current researches, brain edema can be controlled or alleviated by different drugs or treatments. Glucocorticoid is considered to be effective for reducing the permeability of blood-brain barrier and controlling brain edema. Dexamethasone is a widely used corticosteroid for treating brain edema. A lot of experiments showed that short term and high dose application of dexamethasone could depress the activity of nitric oxide synthase and control the formation and the development of brain edema. There are too many side effects that limit the clinical application of dexamethasone at an effective concentration. ( i )High dose application of dexamethasone can influence the normal functions of other organs or systems and result in gastrointestinal bleeding, functional depression of adrenal cortex, hypokalemia, neuropsychiatric symptoms, and so on. (ii )Dexamethasonecan result in the diffusion of infection and other complications, so it is not suitable for patients with epilepsy, pulmonary tuberculosis or gastrointestinal ulcer. (iii)After high dose application of dexamethasone, the drug concentration in plasma is unsteady for metabolism and need to be kept by reduplicate injection. (iv)High dose application of dexamethasone can influence the function of neurons, induce degeneration and facilitate brain aging.In clinic treatment, high dose application of dexamethasone is to obtain higher glucocorticoid content in brain parenchyma and depress the side effects by shortening the period of treatment. According to literatures, the dexamethasone sustained-releasing could control peritumoral brain edema and the sustained-perfusing could alleviate post-traumatic brain edema. Following dexamethasone sustained releasing, drug concentration may be increased persistently and effectively in brain parenchyma and reduced in plasma, so it seems that the drug dynamics of dexamethasone interstitial delivery system is safer. At the same time, its releasing rate can be easily controlled because the releasing velocity is limited by the molecular weight of its carrier material.Objective:In this study, we take advantage of stereotactical technique to establish the rat model with brain edema and dexamethasone sustained-releasing to observe whether this drug interstitial delivery system effects brain edema.1 The model with brain edema and dexamethasone sustained-releasing is established to evaluate the key processes and resolve the potential problems following brain edema.2 To evaluate the effectiveness of this drug delivery system in treating brain edema. If it is effective, complications induced by high dose dexamethasone may be avoided and this drug may be applied to treat more patients with edema.3 NO and nitric oxide synthase (NOS) play very important roles in the processthat brain edema is forming and deteriorating. To define the mechanism that dexamethasone sustained-releasing alleviates brain edema, the change of NOS activity is determined.4 The concentration and the type of glucocorticoid receptors in plasma were thought to be related to the function that dexamethasone control brain edema in some literatures, but in some others, it was found that if animals received dexamethasone sustained-releasing in brain, the drug concentration in plasma was too low. If sustained-releasing dexamethasone can alleviate brain edema in this study, it will be concluded that glucocorticoid receptor in plasma may be irrelevant to this function.Materials and methods:1 According to the method introduced in literatures, dexamethasone sustained release microgranules were manufactured. Dexamethasone acetate and L-polylactic acid were dissolved in chloroform and poured into water. After being mixed, emulsified and solidified, the admixture was vaporized and desiccated, and the primrose polymer containing dexamethasone acetate was obtained. This polymer was shortened to form columned microgranules. Each microgranule was approximately 1.0mm diameter x 1.5mm long and contained 1.25mg dexamethasone acetate.2 Dexamethasone sodium phosphate injection was diluted by normal saline solution from 5mg/ml to 1.31mg/ml. Each rat was injected intraperitoneally with 0.8ml per 6 hours for 24 hours.3 To determine the effectiveness of dexamethasone sustained release microgranules in the treatment of brain edema, the models of Sprague-Dawley rats were constructed. The exposed left parietal lobe was frozen by a liquid-nitrogen-cooled probe outside the meninges for 30 seconds. Four polymers with or without dexamethasone were implanted into the frozen area of each rat by stereotactical technique to control the target and the depthaccurately. All animals were sacrificed 24 hours later.4 Forty-eight Sprague-Dawley male rats, weighted 250 to 280g, were divided randomly and averagely into six groups (group A, B, C, D, E and F). In group A and D, the polymers containing dexamethasone acetate (5mg) were implanted into the left frozen parietal lobe and 0.8ml normal saline solution was injected intraperitoneally per 6 hours for 24hours; The rats in group B, E received polymers without dexamethasone acetate implanted and dexamethasone sodium phosphate injected intraperitoneally (1.05mg per 6 hours, total dose was 4.2mg); In group C, F, the animals received contrast material and normal saline injection. After all animals had been sacrificed, the water content was measured in group A, B, C and NOS activity was determined in group D, E, F.5 Brain water content was measured quantitatively with dry-wet method. Before and after it was parched, the weight of the left hemisphere was quantified by analytical balance. The water content was calculated with Elliott's formula.6 In vivo, nitric oxide is a important neuromodulator. The function of it depends on NOS activity. In this study, NOS activity was determined to definitude the mechanism that dexamethasone sustained release microgranules alleviated brain edema. Above all, the frozen cortex of left hemisphere around the dexamethasone sustained release microgranules was isolated and 10% brain homogenate was fabricated. After centrifugation, the obtained supernatant was diluted and the reagents were transferred into. Absorbency was determined by ultraviolet optical assay and the NOS activity was calculated with referenced formula.Results1 With liquid nitrogen frozen outside the meninges, the rat brain edema model could be induced successfully and there was no rat died. Statistical analysis proved that brain water contents were homogenous distribution in each group.2 The water content(%) in group A, B, C was 80.93 + 2.27, 81.29 + 2.22, 85.54 + 2.69, respectively. It was significant that the brain water contents of group A and B were lower than those of group C (P=0.001, P=0.002), and there was no significant difference (P=0.767) between group A and group B.3 The NOS activity(U/ml) in group D, E, F was 11.50 + 2.41, 12.55 ±2.66, 15.84 + 3.74, respectively. The NOS activity in group D and E dropped contrasting with the control group (P=0.009, P=0.039) and there was no significant difference (P=0.491) between group D and E.Conclusions1 The rat model is stably established with liquid-nitrogen frozen on the exposed left parietal lobe outside the meninges and dexamethasone implanted by stereotactical technique. During the experiment, there was no rat died. It is undoubted that this model is successful, reliable and safe.2 The interstitial delivery of dexamethasone can reduce the water content in brain parenchyma and prevent the development of brain edema.3 The result suggests that brain edema can be effectively controlled by dexamethasone sustained release microgranules implanted into brain parenchyma. To alleviate brain edema, the protective effect of dexamethasone intraperitoneally injected and interstitial delivery is similar. Because the drug concentration in plasma is very lower and functional disturbances of other organs are slighter, the drug dynamics is safer than that with dexamethasone injected.4 Both intraperitoneal injection and interstitial delivery of dexamethasone could depress the NOS activity in edematous hemisphere. It is concluded that the mechanism that interstitial delivery of dexamethasone alleviates brain edema may be associated with the depression of NOS activity in brain parenchyma.5 In addition, it has been reported in some literatures that dexamethasone concentration in plasma was very low following interstitial delivery ofdexamethasone. At the same time, this study proved that these microgranules alleviated brain edema. It is seemed that this function of dexamethasone may be irrelevant to the concentration and the type of glucocorticoid receptors in plasma.
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