Introduction

Traumatic brain injury (TBI) is a leading health problem in both develo** and high-income countries. Over 50 million TBIs occur internationally each year, causing one-third of injury-related deaths and costing 0.5% of worldwide GDP [1]. TBI-related disability has an incidence of approximately 4 million people in the USA. This disease disproportionally affects the young, with peaks in the adolescent and the elderly stages of life [2]. These numbers underestimate the true impact of TBIs, with an order of magnitude more going unreported and unnoticed [2, 3].

Traumatic brain injury is a complex heterogeneous pathology with a wide clinical impact, ranging from asymptomatic to a neurologically devastating disease. Severe TBI has been estimated to have a mortality rate of almost 40%. Those who survive are often debilitated with severe physical, emotional, and economic burdens [4]. Nearly half of TBI survivors develop depression and later in life suffer from dementia at five times the average rate [5]. Even mild TBIs can have long-term impacts including increased risk of dementia, seizures [6], functional limitations, disability, mood disorders [7], and reduced quality of life [8].

Crucial to the management of TBI is recognition that it is not an acute condition, but a chronic and evolving disease process. The “second hit” model posits that damage continues even after the original injury, as swelling and inflammation sets in. Additionally, the recovery process is a complex, poorly understood process dependent on the resha** or reformation of the damaged neural networks [9].

The standard of care for TBI management is a constantly changing field. In the acute period, surgical intervention such as placement of a ventriculostomy or craniectomy can have a significant impact on morbidity and mortality [10, 11]. However, the vast majority of cases are managed conservatively [10]. In addition to long-term support including physical and occupational therapy, many different medical interventions have been tried. Aside from antiepileptics prevention of early-onset seizures [12] and multimodal therapy for intracranial pressure control [13], no other regimen has been codified in the management of TBI sequelae [14, 15].

This large divide between a clear clinical need and a lack of solution has driven an enormous amount of research into potential treatments. Clinical trials have investigated a wide variety of known medications [15], such as magnesium [16] and cyclosporine-A [17]. One class of medications receiving increased interest is statins. Statins classically impact physiology as inhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-controlled step within the mevalonate pathway. This interrupts the metabolic chain reaction that eventually produces cholesterol and other organic isoprenoid derivates such as steroids and vitamins. However, further investigations have revealed many alternative impacts of statins, including stimulating angiogenesis, anti-inflammatory effects, and influence of neural circuit formation (Fig. 1) [18].

Fig. 1
figure 1

The putative beneficial effects and proposed mechanisms of statin therapy for TBI

Full size image

History

In the late twentieth century, researchers began to elucidate the role of cholesterol in cardiovascular disease and looked for ways to control cholesterol levels. The first statin was actually a byproduct of antibiotic research. Inspired by the discovery of penicillin, researchers were culturing fungi at a large scale to find new compounds. Mevastatin, also known as compactin, was isolated in 1971 from the fungus Penicillium citrinum by researchers looking for an enzyme that might target microbes that depended on sterols or other isoprenoids [19, 20]. Lovastatin was isolated by Merck in 1978 from Aspergillus terreus and in 1987 became the first statin to be approved by the FDA. The incredible results of early trials [21] caused a wave of public interest in statins, leading to the development of many alternative compounds. In the early 2000s, blockbuster drugs such as simvastatin, pravastatin, and atorvastatin had an average annual cost of nearly $25 billion in the USA alone [22].

Mechanism of Action

Statins were originally discovered for their ability to competitively inhibit HMG-CoA reductase due to their molecular similarity to HMG-CoA (Fig. 2). This competition for the enzyme’s active site allows it to compete with the native substrative and reduce the rate that mevalonate is produced. The lower availability of mevalonate decreases the body’s ability to generate cholesterol (a downstream molecule). This impact is compounded by the liver, which increases the production of LDL receptors to harvest circulating cholesterol, further lowering bloodstream levels [23].

Fig. 2
figure 2

The cholesterol synthetic pathway, highlighting the effects of statins on the mevalonate pathway. PP pyrophosphate, HGM 3-hydroxy-3-methylglutaryl, CoA coenzyme A

Full size image

Yet as their use became more widespread, new findings began to suggest that this is not the only action of statins in the body. In fact, a large part of its impact may actually be derived from other sources. For example, simply lowering cholesterol by other means does not have the same benefit, and these drugs have been shown to have a benefit in disease processes not classically associated with elevated lipid levels [24].

More than 20 years since statins were put on the market, new findings demonstrated that many of their health benefits may be through their immunomodulatory impact. For example, they are known to inhibit the inductive effect of interferon-γ on major histocompatibility class II (MHC-II), thereby repressing MHC-II-medicated T-cell activation [25]. They have also been shown to lower C reactive protein (CRP) levels by one-third [26], as well as other inflammatory markers such as inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) [27]. Other studies have shown a disruption of lipid rafts, preventing the organization of proteins necessary for the activation of immune cells [28]. Natural killer cells have lower cytotoxicity in patients on statins, leading to their use in preventing organ rejection [29]. Other autoimmune disorders that have been treated with statins include multiple sclerosis, rheumatoid arthritis, and osteoporosis [25].

Further investigations have also shown a direct impact on vasculature. Endothelial-dependent flow significantly improves after statin treatment [30]. Statins induce endothelial nitric oxide synthase (eNOS), an enzyme that generates nitric oxide (NO) within vessel walls to promote vascular relaxation and decrease interactions with circulating leukocytes and platelets [31]. They also induce the expression of various genetic profiles involved in the remodeling of both endothelial and smooth muscle cells [24].

Lastly, there may be direct neurological impacts both cholesterol and non-cholesterol mediated. Cholesterol is a major component of neural membranes and is a rate-limiting step in synaptogenesis [32]. Compactin has been shown to promote the maintenance of dendritic and axonal connectivity patterns [33]. Statins can protect neurons from excitotoxic damage, such as NMDA-mediate excitotoxic cell death [34]. Simvastatin in particular has been shown to stimulate the Bcl-2 gene, promoting neuronal survival [35] and attenuating axonal injury [76]. However, not all studies are uniformly positive. Robertson et al. performed a phase II clinical trial and found that atorvastatin for 7 days had no difference in the Rivermead score (a post-concussive assessment) at 3 months post-injury [77]. Notably, as with some of the animal studies, these trials have shown the effective time window to be as long as 24 h post-injury, increasing the clinical utility of statins in real-world situations.

Other studies aimed to correlate these outcomes with physiologic parameters of injury. From the inflammatory perspective, statins were shown to reduce levels of tumor necrosis factor- α (TNF-α), with mixed results on interleukin (IL) levels [67, 68]. Similarly, simvastatin has been shown to lower CRP in severe TBIs requiring ICU admission [69]. Interestingly, even in patients that show long-term benefits, it is difficult to notice any immediate difference on cranial imaging, with similar contusion volumes and rates of expansion [73], though one study showed decreased cortical loss [78].

Lastly, atorvastatin will be tested in a multi-arm, multi-stage adaptive platform trial for the acute treatment of TBI by the TRACK-TBI network. This will be a multi-center, double-blind, placebo-controlled adaptive platform, precision medicine trial conducted under a single multi-arm, multi-stage (MAMS) study with parallel groups. Subjects will be randomized to receive one of four possible treatments, being atorvastatin a study drug. It is expected that the findings of this study will assist in clarifying the potential beneficial effect of statins in the management of TBI (Table 2).

Table 2 Human studies of TBIs
Full size table

Conclusion

TBI is a significant and growing public health problem. There is no current standard of care regimen in the medical management of TBI. Statins are a well-studied popular class of medication with minimal side effect profile relative to the proposed benefits. Recent research has demonstrated that their benefits are not limited solely to the cardiovascular outcomes. In vitro, animal, retrospective, and randomized control studies have all demonstrated the potent for multimodal impact on both motor and cognitive outcomes. Further work is needed to clarify how to maximize its impact to ensure that its putative and potential benefits are realized.