Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury

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Abstract

The treatment of traumatic brain injury (TBI) remains limited, and aside from surgical hematoma evacuation, clinical management is largely supportive and directed toward management of cerebral edema and intracranial hypertension. Secondary neuronal injury caused by ischemia and the development of cerebral edema may occur in the subacute phase, with intracranial pressures often peaking in the first several days following injury. Because inflammation contributes significantly to the pathophysiology of cerebral ischemia and endothelial dysfunction underlies the development of cerebral edema, therapeutic strategies that target the post-traumatic inflammatory cascade and reduce endothelial dysfunction hold enormous potential to improve clinical outcomes after TBI. Statins inhibit inflammation by suppressing inflammatory cytokine release, and by interfering with multiple steps of leukocyte recruitment and migration into the CNS. In this study, we demonstrate that treatment with atorvastatin and simvastatin markedly reduced functional neurological deficits after traumatic brain injury in mice. These effects were accompanied by histological reduction in degenerating hippocampal neurons and suppression of inflammatory cytokine mRNA expression in brain parenchyma. Furthermore, statin treatment improved cerebral hemodynamics following head injury. Thus, the administration of statins may represent a viable therapeutic strategy in the acute treatment of closed head injury.

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability, with an estimated annual cost of 60 billion dollars in the United States alone (Finkelstein et al., 2006). Aside from surgical hematoma evacuation, treatment remains largely supportive and is directed towards management of cerebral edema and intracranial hypertension with osmotic agents, hyperventilation, and ventricular drainage (Bulger et al., 2002). None of these interventions has been demonstrated to significantly improve long-term functional outcome (Biros and Heegaard, 2001) and there remains a compelling need for more effective therapeutic options in this patient population.

Brain trauma is associated with a neuroinflammatory response characterized by microglial and astrocytic activation, as well as release of reactive oxygen species and inflammatory mediators. In particular, pro-inflammatory cytokines such as IL-6 and TNFα have been suggested to play an important role in early events mediating blood–brain barrier breakdown and subsequent development of cerebral edema (Ramilo et al., 1990). Secondary neuronal injury caused by ischemia and the development of cerebral edema may occur in the subacute phase, with intracranial pressures often peaking in the first several days following injury. Thus, therapeutic strategies that target the post-traumatic inflammatory cascade hold enormous potential to improve outcomes after TBI.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, referred to as “statins”, are potent inhibitors of cholesterol biosynthesis (Goldstein and Brown, 1990). There is growing clinical evidence that the statin class of drugs may have additional properties that are potentially neuroprotective independent of their effect on serum cholesterol (Cucchiara and Kasner, 2001, Rikitake and Liao, 2005). Mevalonic acid, the product of HMG-CoA reductase, is the precursor for key cellular isoprenoid compounds in addition to cholesterol. By inhibiting the production of one or more of these compounds, statins have been demonstrated to exert anti-inflammatory effects, which may be palliative in the setting of acute brain injury (Weitz-Schmidt et al., 2001).

Cerebral hypoperfusion and ischemia are also important causes of secondary neuronal injury following TBI, and impaired vascular responses have been described in both the preclinical and clinical settings (Hlatky et al., 2003). For example, following head injury there is an impairment of autoregulation (i.e. the ability of an organ to maintain constant tissue blood flow despite changes in perfusion pressure) and an inability of pial arterioles to respond to normal changes in PCO2 and PO2 (Wei et al., 1980). One mechanism by which statins improve cerebral blood flow is via selective upregulation of endothelial nitric oxide synthase (eNOS) (Amin-Hanjani et al., 2001, Laufs et al., 1998). We have previously demonstrated robust upregulation of eNOS following statin administration in the injured brain (McGirt et al., 2002), and statin-induced upregulation of eNOS activity also may be expected to reduce ischemic injury following trauma.

Thus, there are several possible mechanisms by which the administration of statins might be expected to reduce neurological injury following trauma. Although the anti-inflammatory and vasoactive effects of statins likely represent a class effect of HMG-CoA reductase inhibitors, we chose atorvastatin and simvastatin because of their common clinical use and different pharmacokinetic properties. Atorvastatin has a longer peripheral plasma elimination half-life compared to simvastatin (7 h vs. 3 h or less, respectively) (Lennernas, 2003, Lennernas and Fager, 1997). Furthermore, atorvastatin inhibits HMG-CoA reductase even longer (20–30 h) due to the contribution of its active metabolites. Based on the known vasoactive and anti-inflammatory properties of HMG-CoA reductase inhibitors, we hypothesized that administration of these statins would attenuate neuronal injury and improve functional outcome in a clinically relevant murine model of closed head injury.

Section snippets

Closed head injury model (CHI)

This murine CHI model (Lynch et al., 2005a, Lynch et al., 2005b) was adapted from a previously described model of closed cranial trauma for the rat (Foda and Marmarou, 1994). Twelve- to fourteen-week-old C57Bl/6J male mice (Jackson Laboratories, Bar Harbor, ME) were used. After anesthesia induction with 4.6% isoflurane, the trachea was intubated and the lungs were mechanically ventilated with 1.6% isoflurane in 30% O2/70% N2. Rectal temperature was maintained at 37 °C. The animal was positioned

Statin pretreatment is associated with reduced histological deficit and improved vestibulomotor function following head injury

There were no differences in physiological variables between groups receiving statin pretreatment or vehicle at baseline or 10 min post-traumatic brain injury with regard to body weight, mean arterial pressure, glucose, and arterial pH, PaCO2, PaO2, and HCO3 (Table 1). Pretreatment with either simvastatin or atorvastatin was associated with a significant improvement vestibulomotor function after injury, as quantified by Rotorod latency (p < 0.05; Fig. 1A). Both atorvastatin and simvastatin

Discussion

In this study, we demonstrate that parenteral treatment with two HMG-CoA reductase inhibitors, atorvastatin and simvastatin, markedly reduced functional neurological deficits after traumatic brain injury in mice. These effects were accompanied by improvement in short-term and long-term functional performance, reduction in degenerating hippocampal neurons, and suppression of inflammatory cytokine mRNA in traumatized brain. Furthermore, statin pretreatment reduced the marked reduction in cerebral

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