N-acetylcysteine amide confers neuroprotection, improves bioenergetics and behavioral outcome following TBI

Abstract

Traumatic brain injury (TBI) has become a growing epidemic but no approved pharmacological treatment has been identified. Our previous work indicates that mitochondrial oxidative stress/damage and loss of bioenergetics play a pivotal role in neuronal cell death and behavioral outcome following experimental TBI. One tactic that has had some experimental success is to target glutathione using its precursor N-acetylcysteine (NAC). However, this approach has been hindered by the low CNS bioavailability of NAC. The current study evaluated a novel, cell permeant amide form of N-acetylcysteine (NACA), which has high permeability through cellular and mitochondrial membranes resulting in increased CNS bioavailability. Cortical tissue sparing, cognitive function and oxidative stress markers were assessed in rats treated with NACA, NAC, or vehicle following a TBI. At 15 days post-injury, animals treated with NACA demonstrated significant improvements in cognitive function and cortical tissue sparing compared to NAC or vehicle treated animals. NACA treatment also was shown to reduce oxidative damage (HNE levels) at 7 days post-injury. Mechanistically, post-injury NACA administration was demonstrated to maintain levels of mitochondrial glutathione and mitochondrial bioenergetics comparable to sham animals. Collectively these data provide a basic platform to consider NACA as a novel therapeutic agent for treatment of TBI.

Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats

“…NACA did not affect the levels of peroxynitrite at either time point, corroborating results in moderate TBI studies [19]. Peroxynitrite forms by excessive levels of superoxide and NO.…”

“…The study was designed primarily to assess NACA in a focally severe form of TBI, given the previously stated beneficial effects in relation to NAC in other TBI models [19]. For this reason, NAC was not included in this study.…”

“…NACA permeates cellular and mitochondrial membranes, crosses the blood-brain barrier [16,17] and has higher radical scavenging ability, metal chelating activity and reducing power than NAC [18]. In moderate TBI, NACA treatment improves mitochondrial bioenergetics, cognitive function, cortical tissue sparing and reduces lipid peroxidation product 4-hydroxynonenal compared to NAC or vehicle treated rats [19]. In acute spinal cord injury, NACA treatment improves mitochondrial bioenergetics, maintains mitochondrial glutathione and improves tissue sparing and hind limb function [20].…”

Systematic Review of Traumatic Brain Injury and the Impact of Antioxidant Therapy on Clinical Outcomes

“…Although there are numerous experimental studies showing significant effects of antioxidants in reducing secondary injury using animal models (Ding et al, 2014;Pandya et al, 2014;Senol et al, 2014), evidence generated from the reviewed clinical studies is somewhat limited. Future research should focus on effectively translating findings from experimental studies into practice.…”

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

“…36,37 ABCB1 (also known as MDR1 or P-glycoprotein) has been studied more so than ABCC1. ABCB1 is a prominent component of the dynamic BBB, with substrates relevant to the management of TBI that include opioids (e.g., morphine, fentanyl), anti-epileptics (e.g., phenytoin), and antibiotics (e.g., vancomycin).…”