Effects of Usage of Simvastatin in Mild to Moderate Traumatic Brain Injury (TBI) Patients. Could it Make a Difference?

TBI is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force.

[A] Alteration in brain function is defined as 1 of the following clinical signs:

• Any period of loss of or a decreased level of consciousness.
• Any loss of memory for events immediately before (retrograde amnesia) or after the injury (Post traumatic amnesia)
• Neurologic deficits (weakness, loss of balance, change in vision, dyspraxia paresis/plegia [paralysis], sensory loss, aphasia, etc.)
• Any alteration in mental state at the time of the injury (Confusion, disorientation, slowed thinking, etc.) [B] or other evidence of brain pathology: Such evidence may include visual, neuroradiologic, or laboratory confirmation of damage to the brain.

Traumatic brain injury is the most common cause of death and disability in young people.

Traumatic brain injury is graded as mild, moderate, or severe on the basis of the level of consciousness or Glasgow coma scale (GCS) score after resuscitation. Mild traumatic brain injury (GCS 13-15) is in most cases a concussion and there is full neurological recovery, although many of these patients have short-term memory and concentration difficulties. In moderate traumatic brain injury (GCS9-13) the patient is lethargic or stuporous, and in severe injury (GCS 3-8) the patient is comatose, unable to open his or her eyes or follow commands.

The World Health Organization (WHO) estimates that almost 90% of deaths due to injuries occur in low- and middle-income countries (LMICs), where the 85% of population live and this situation will continue to represent an important global health problem in the upcoming years. Of these trauma-related deaths TBI is the main cause of one-third to one-half, and the leading cause of disability under forty years-old (15-20/100,000 populations per year).

One of the most significant disabilities associated with TBI is short- and long-term cognitive deficits. Approximately 65% of patients with moderate to severe TBI report long-term problems with cognitive functioning, and as many as 15% with mild TBI have persistent problems that often include cognitive deficits .These deficits interfere with work and daily living activities, exacting a personal and economic cost that is difficult to quantify. However, despite substantial efforts, few therapeutic options exist to prevent or alleviate cognitive dysfunction after TBI in humans.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, also known as "statins," are an ideal candidate therapy for acute brain injury. Statins influence multiple mechanisms of acute and secondary neuronal injury; they have endothelial and vasoactive properties, as well as anti-oxidant, anti-inflammatory, anti-excitotoxicity, and anti-thrombotic effects. Statin treatment would be practical to implement in TBI because Statins have wide availability, Food and Drug Administration approval, a favorable adverse event profile, and a track record of safety in critically ill populations.

CLASSIFICATION OF STATINS All statins contain an HMG-like component that binds to HMG-CoA reductase.other molecular characteristics vary across the class, including potency, lipophilicity, metabolism, and pharmacokinetics. Lovastatin, pravastatin, and simvastatin are obtained from fungi; atorvastatin, rosuvastatin, fluvastatin, and pravastatin are synthetic. Statin potency refers to the degree of HMG-CoA reductase inhibition. Statins are potent inhibitors of cholesterol biosynthesis via HMG-CoA reductase inhibition. Statins are widely used to decrease low-density lipoprotein (LDL) levels and lower the risk of cardiovascular events. As clinical experience with statins has increased, evidence suggests that the cardiovascular benefit may not solely be related to cholesterol lowering, but also to systemic and vascular anti-inflammatory effects. There is growing evidence that statins have additional properties that are neuroprotective, also independent of serum cholesterol effects. The therapeutic effects of statins in brain injury may be divided according to mechanism from most acute to more chronic: acute lesional effects, anti-inflammatory and anti-excitotoxic effects, vascular and endothelial effects, anti-apoptotic effects, and effects on neurogenesis and angiogenesis The statins are inhibitors of cholesterol biosynthesis, and they have additional pleiotropic properties that make them attractive multipotential neuroprotective drugs. Statins increase endothelium-derived nitric oxide production and reduce vascular inflammation, thereby improving the microvasculature after traumatic insult. In in vitro models statins protect cortical neurons from NMDA-induced excitotoxic death , and statin treatment significantly improves neuronal survival following TBI .Statins may also promote the growth and differentiation of new neurons after brain injury , and their ability to increase neurogenesis may be in part due to up regulation of neurotrophic factors (e.g. BDNF) Notably, statins exert powerful anti-inflammatory effects, in part by decreasing the formation of isoprenoids In TBI models, statins have been shown to significantly reduce proinflammatory cytokine production and attenuate microglial activation and cerebral edema formation, while increasing BBB integrity. Experimental studies have shown that statins target multiple secondary injury pathways and significantly improve functional recovery after TBI. Furthermore, the therapeutic window for this class of drugs is relatively large, with treatment 24 h after TBI resulting in long-term functional improvements and reduced neuronal cell loss . As such, statins possess key preclinical neuroprotective characteristics that make them suitable candidates for clinical translation. Importantly, statins have a long clinical track record in critically ill patients; they are easy to administer, are well tolerated and have well-defined side effects . A small prospective, randomized, double-blind clinical trial in TBI has been performed using the statin drug rosuvastatin, and treatment showed modest improvements in TBI associated amnesia and disorientation time outcomes .