Elsevier

Surgical Neurology

Volume 72, Issue 2, August 2009, Pages 146-152
Surgical Neurology

Trauma
Atorvastatin efficiency after traumatic brain injury in rats

https://doi.org/10.1016/j.surneu.2008.07.004Get rights and content

Abstract

Background

The neuroprotective effects of statins possibly depend on their pleiotropic effect such as antioxidative and anti-inflammatory properties. In this study, we have evaluated the efficiency of atorvastatin on brain edema, lipid peroxidation, and ultrastructural changes in TBI animal model.

Methods

Modified Feeney method has been used for the trauma model in rats. Only craniectomy for group A and trauma after craniectomy for group B was the procedure for animals. For the trauma, rods weighing 24 g were dropped on a foot plate just over the dura. Atorvastatin (1 mg/kg, IP) was administered to the animals in group C after craniectomy and trauma; but on the other hand, animals in group D received only 0.5 mL PEG as the vehicle. Brains were harvested 24 hours after the trauma for the assays of wet-dry weight, lipid peroxidation level, and ultrastructural investigations. Lipid peroxidation levels, TEM, and UNGS were the investigated parameters. The statistical comparisons between the groups were investigated by 1-way ANOVA and post hoc analysis by Duncan and Dunnett T3 test within the groups at the significance level P = .05.

Results

Trauma increased water contents of the brain tissues and lipid peroxidation levels in groups B and D. When compared with the results of group B (brain edema, 84.694% ± 1.510%; lipid peroxidation, 74.932 ± 2.491 nmol/g tissue), atorvastatin (1 mg/kg) significantly decreased brain edema (77.362% ± 1.448%), lipid peroxidation level (58.335 ± 3.980 nmol/g tissue), and UNGS scores in group C (P < 0.05).

Conclusion

In this descriptive study, the remarkable improvements of atorvastatin on brain edema, lipid peroxidation, and ultrastructural investigations encouraged us for a further dose optimization study.

Introduction

The HMG-CoA reductase inhibitors, statins, have neuroprotective effects in addition to their original role in lowering cholesterol. During the last decade, the beneficial effects of statins after ischemic and TBI [19], [23], [30], autoimmune diseases [18], [38], and Alzheimer disease[31] have been investigated by many independent research groups. Although the mechanisms that underlie the neuroprotective properties of the statins are still not fully elucidated, the possible mechanisms suggested being the pleiotropic effects such as antioxidative and anti-inflammatory properties of the statins [34].

The brain injury formed as a result of head trauma involves an initial mechanical damage followed by a sequence of biomolecular pathways resulting in secondary brain injury. Oxygen free radical–mediated lipid peroxidation, inflammation, and brain edema formation appear to be fundamental mechanisms of secondary damage in TBI [15], [26], [32].

Extracellular accumulation of glutamate and stimulation of glutamate receptors may be the possible results of cerebral energy supply inhibition, which ends in neuronal degeneration. Traumatic brain injury causes a deficiency of local energy, extracellular glutamate accumulation, and excitotoxic lesion, which is reducible by glutamate receptor antagonists. Excitotoxicity on the neuronal cells is partly mediated by the overactivation of the N-methyl-d-aspartate type glutamate receptors. This overactivation leads to the excessive influx of Ca++ through the receptor-mediated ion channel and subsequent free radical formation resulting in possible destruction in cellular structure [21], [22], [27], [29].

Brain edema, which is an important therapeutic target after TBI in humans, strongly influences survival and secondary tissue damage during the acute phase after TBI.

Atorvastatin, a member of the statin family, has been shown to be neuroprotective after TBI in rats [2], [16]. In this study, to elucidate the mechanisms underlying the neuroprotective effect of atorvastatin, we investigated its impact on lipid peroxidation and brain edema after TBI in rats.

Section snippets

Materials

The drug substance atorvastatin was from Dr Reddy's (India). For the systemic treatment groups, atorvastatin formulation was prepared by using PEG (Sigma, USA). For anesthesia, a mixture of Rompun® (Bayer Healthcare, Turkey) and Ketalar® (Pfizer Drug LtdCo, Turkey) were used.

Animal model

The experimental protocol was approved by the Local Ethical Committee of Hacettepe University. Male SD rats (n = 72), weighing 200 to 250 g, were allocated randomly into 4 groups, with 18 rats in each group as follows in

Discussion

It has been shown that TBI results in increased extracellular concentrations of glutamate not only in experimental studies but also in humans [5], [12]. Bullock et al [5] has conducted a prospective research on 80 patients with severe head injury, and they have reported that extracellular amino acids are increased 10 to 20 times higher in contused cortex when compared to the noncontused cortex [6]. The extracellular accumulation of glutamate and the overstimulation of their receptors are the

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