Drug Repurposing in the Treatment of Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is the most common cause of morbidity among trauma patients; however, an effective pharmacological treatment has not yet been approved. Individuals with TBI are at greater risk of developing neurological illnesses such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The approval process for treatments can be accelerated by repurposing known drugs to treat the growing number of patients with TBI. This review focuses on the repurposing of N-acetyl cysteine (NAC), a drug currently approved to treat hepatotoxic overdose of acetaminophen. NAC also has antioxidant and anti-inflammatory properties that may be suitable for use in therapeutic treatments for TBI. Minocycline (MINO), a tetracycline antibiotic, has been shown to be effective in combination with NAC in preventing oligodendrocyte damage. (−)-phenserine (PHEN), an anti-acetylcholinesterase agent with additional non-cholinergic neuroprotective/neurotrophic properties initially developed to treat AD, has demonstrated efficacy in treating TBI. Recent literature indicates that NAC, MINO, and PHEN may serve as worthwhile repositioned therapeutics in treating TBI.

In Silico and Ex Vivo Analyses of the Inhibitory Action of the Alzheimer Drug Posiphen and Primary Metabolites with Human Acetyl- and Butyrylcholinesterase Enzymes

“…Parenthetically, phenserine demonstrates pharmacologically valuable AChE inhibition when administered to animals and humans, 38 , 43 − 45 in addition to useful non-cholinergically mediated actions. 26 , 46 However, it is AChE inhibition that likely also underpins phenserine’s dose-limiting actions. 44 In contrast, Posiphen lacks AChE inhibitory action and hence can be escalated to a higher dose in both humans and rodents.…”

“… 6 Phenserine, initially developed as an oral, immediate release, AChE inhibitor that proved well tolerated in human studies (645 subjects for up to 1 year) and demonstrated an efficacy signal in AD, 27 − 29 , 45 , 48 has in recent studies demonstrated far more interesting pharmacological action by mitigating programmed neuronal cell death, synaptic loss, and neuroinflammation across multiple cellular and animal neuronal injury models at clinically translatable doses. 26 , 46 , 49 − 53 As a consequence and to optimize these more recent cholinergically and non-cholinergically mediated pharmacological actions, phenserine has re-entered clinical development as an extended controlled-release oral tablet formulation to maintain steady-state therapeutic drug levels and AChE inhibition in AD and traumatic brain injury human clinical trials. 54 In contrast, Posiphen was originally developed as a “cholinergically inert” APP synthesis inhibitor to lower Aβ generation and subsequent tau phosphorylation and associated neuroinflammation, 47 which have been confirmed by recent studies by others.…”

Neuroprotection treatment in traumatic brain injury - right now or later on?

“…5). Pomimo dobrego wyrównania parametrów życiowych i elektrolitowych, niewystępowania cech infekcji, prowadzonego leczenia tywniejszych metod leczenia farmakologicznego TBI w fazie ostrej oraz redukujących ryzyko odległych powikłań, zwłaszcza u chorych z dominującymi zaburzeniami świadomości [25].…”

CCL5 via GPX1 activation protects hippocampal memory function after mild traumatic brain injury

“…These suggest the importance of antioxidant activation and immune response balance for recovery after brain injury. Indeed, both preclinical and clinical studies have found positive effects of NAC in several TBI models, including the weight drop model used here [ 5 , 6 , 8 , 9 ].…”