Restricted accessResearch articleFirst published online 2026-1
CMX-2043 Treatment Limits Neural Injury Pathophysiology and Promotes Neurological and Cognitive Recovery in a Pediatric Porcine Traumatic Brain Injury Model
Traumatic brain injury (TBI) represents a major global health issue contributing to significant disability and mortality. The TBI-induced secondary injury cascade, characterized by neuroinflammation, neural cell death, and tissue damage, results in lifelong functional deficits. Alpha-N-[(R)-1, 2-dithiolane-3-pentanoyl]l-glutamyl-l-alanine (CMX-2043) is a novel alpha lipoic acid (ALA)-based therapeutic that has neuroprotective, anti-apoptotic, and anti-inflammatory properties that mitigate cellular, tissue, and functional deficits following TBI. In this study, we evaluated the therapeutic efficacy of CMX-2043 on neural injury severity and functional recovery in a clinically relevant porcine TBI model. CMX-2043 was administered 1-h post-TBI subcutaneously (SQ; n = 8) or intravenously (IV; n = 8) for a total of 5 days. Control piglets (placebo; n = 11) received saline subcutaneously. Magnetic resonance imaging (MRI), immunohistochemistry analysis, modified Rankin Scale (mRS) neurological evaluation, and social recognition testing (SRT) were evaluated up to 42 days post-TBI. MRI revealed that SQ and IV CMX-2043 administration reduced hemispheric swelling and atrophy, lesion volume, midline shift, and intracerebral hemorrhage and preserved diffusivity, cerebral blood flow, and white matter integrity. CMX-2043-mediated neuroprotection and regeneration were indicated by increased neural cell density, decreased neuroinflammation, and enhanced neurogenesis following SQ and IV administration. These cellular and tissue-level changes corresponded with reduced neurological deficits and rapid cognitive recovery as indicated by improved mRS and SRT results, respectively. Collectively, these results observed in a translational large animal porcine model suggest that CMX-2043 holds significant clinical value to potentially mitigate TBI pathophysiology and promote functional recovery.
Centers for Disease Control and Prevention. National Center for Health Statistics: Mortality data on CDC WONDER. 2025.
3.
DewanMC, RattaniA, GuptaS, et al.Estimating the global incidence of traumatic brain injury. J Neurosurg, 2019; 130(4):1080–1097; doi: 10.3171/2017.10.JNS17352
4.
NgSY, LeeAYW. Traumatic brain injuries: Pathophysiology and potential therapeutic targets. Front Cell Neurosci, 2019; 13:528; doi: 10.3389/fncel.2019.00528
Center for Disease Control and Prevention. Report to Congress. The Management of Traumatic Brain Injury in Children, National Center for injury Prevention and Control. Atlanta, GA. 2018.
7.
NelsonCA. THe Neurobiological Bases of Early Intervention. In: Handbook of Early Childhood Intervention, Second Edition. (ShonkoffJP, MeiselsSJ. eds.) Cambridge University Press: 2011; pp. 204–229.
8.
KhatriN, SumadhuraB, KumarS, et al.The complexity of secondary cascade consequent to traumatic brain injury: Pathobiology and potential treatments. Curr Neuropharmacol, 2021; 19(11):1984–2011; doi: 10.2174/1570159X19666210215123914
9.
MaasAI, MenonDK, LingsmaHF, et al.Re-orientation of clinical research in traumatic brain injury: Report of an international workshop on comparative effectiveness research. J Neurotrauma, 2012; 29(1):32–46; doi: 10.1089/neu.2010.1599
10.
MarguliesS, HicksR, Combination Therapies for Traumatic Brain Injury Workshop L. Combination therapies for traumatic brain injury: Prospective considerations. J Neurotrauma, 2009; 26(6):925–939; doi: 10.1089/neu.2008.0794
11.
NarayanRK, MichelME, AnsellB, et al.Clinical trials in head injury. J Neurotrauma, 2002; 19(5):503–557; doi: 10.1089/089771502753754037
12.
ChoiKH, ParkMS, KimHS, et al.Alpha-lipoic acid treatment is neurorestorative and promotes functional recovery after stroke in rats. Mol Brain, 2015; 8:9; doi: 10.1186/s13041-015-0101-6
13.
DengH, ZuoX, ZhangJ, et al.Alpha-lipoic acid protects against cerebral ischemia/reperfusion-induced injury in rats. Mol Med Rep, 2015; 11(5):3659–3665; doi: 10.3892/mmr.2015.3170
14.
LvC, MaharjanS, WangQ, et al.alpha-Lipoic acid promotes neurological recovery after ischemic stroke by activating the Nrf2/HO-1 pathway to attenuate oxidative damage. Cell Physiol Biochem, 2017; 43(3):1273–1287; doi: 10.1159/000481840
15.
OzbalS, CankurtU, TugyanK, et al.The effects of alpha-lipoic acid on immature rats with traumatic brain injury. Biotech Histochem, 2015; 90(3):206–215; doi: 10.3109/10520295.2014.977950
16.
TokluHZ, HakanT, BiberN, et al.The protective effect of alpha lipoic acid against traumatic brain injury in rats. Free Radic Res, 2009; 43(7):658–667; doi: 10.1080/10715760902988843
17.
TokluHZ, HakanT, CelikH, et al.Neuroprotective effects of alpha-lipoic acid in experimental spinal cord injury in rats. J Spinal Cord Med, 2010; 33(4):401–409; doi: 10.1080/10790268.2010.11689719
18.
WeiW, WangH, WuY, et al.Alpha lipoic acid inhibits neural apoptosis via a mitochondrial pathway in rats following traumatic brain injury. Neurochem Int, 2015; 87:85–91; doi: 10.1016/j.neuint.2015.06.003
19.
XiaD, ZhaiX, WangH, et al.Alpha lipoic acid inhibits oxidative stress-induced apoptosis by modulating of Nrf2 signalling pathway after traumatic brain injury. J Cell Mol Med, 2019; 23(6):4088–4096; doi: 10.1111/jcmm.14296
20.
StaykovH, LazarovaM, HassanovaY, et al.Neuromodulatory mechanisms of a memory loss-preventive effect of alpha-lipoic acid in an experimental rat model of dementia. J Mol Neurosci, 2022; 72(5):1018–1025; doi: 10.1007/s12031-022-01979-y
21.
KoCY, XuJH, LoYM, et al.Alleviative effect of alpha-lipoic acid on cognitive impairment in high-fat diet and streptozotocin-induced type 2 diabetic rats. Front Aging Neurosci, 2021; 13:774477; doi: 10.3389/fnagi.2021.774477
22.
RocamondeB, ParadellsS, BarciaJM, et al.Neuroprotection of lipoic acid treatment promotes angiogenesis and reduces the glial scar formation after brain injury. Neuroscience, 2012; 224:102–115; doi: 10.1016/j.neuroscience.2012.08.028
23.
WuMH, HuangCC, ChioCC, et al.Inhibition of peripheral TNF-alpha and downregulation of microglial activation by alpha-lipoic acid and etanercept protect rat brain against ischemic stroke. Mol Neurobiol, 2016; 53(7):4961–4971; doi: 10.1007/s12035-015-9418-5
24.
XieX, ShuR, YuC, et al.Mammalian AKT, the emerging roles on mitochondrial function in diseases. Aging Dis, 2022; 13(1):157–174; doi: 10.14336/AD.2021.0729
25.
LaderAS, BaguisiA, CasaleR, et al.CMX-2043 mechanisms of action in vitro. J Cardiovasc Pharmacol, 2016; 68(3):241–247; doi: 10.1097/FJC.0000000000000408
26.
BaguisiA, CasaleRA, KatesSA, et al.CMX-2043 efficacy in a rat model of cardiac ischemia-reperfusion injury. J Cardiovasc Pharmacol Ther, 2016; 21(6):563–569; doi: 10.1177/1074248416640118
27.
BakerEW, KinderHA, HutchesonJM, et al.Controlled Cortical impact severity results in graded cellular, tissue, and functional responses in a piglet traumatic brain injury model. J Neurotrauma, 2019; 36(1):61–73; doi: 10.1089/neu.2017.5551
28.
ChastainCA, OyoyoUE, ZippermanM, et al.Predicting outcomes of traumatic brain injury by imaging modality and injury distribution. J Neurotrauma, 2009; 26(8):1183–1196; doi: 10.1089/neu.2008.0650
29.
SmithermanE, HernandezA, StavinohaPL, et al.Predicting outcome after pediatric traumatic brain injury by early magnetic resonance imaging lesion location and volume. J Neurotrauma, 2016; 33(1):35–48; doi: 10.1089/neu.2014.3801
30.
O’BrienNF, MaaT, Moore-ClingenpeelM, et al.Relationships between cerebral flow velocities and neurodevelopmental outcomes in children with moderate to severe traumatic brain injury. Childs Nerv Syst, 2018; 34(4):663–672; doi: 10.1007/s00381-017-3693-6
31.
WangQ, LvC, SunY, et al.The role of alpha-lipoic acid in the pathomechanism of acute ischemic stroke. Cell Physiol Biochem, 2018; 48(1):42–53; doi: 10.1159/000491661
32.
FuB, ZhangJ, ZhangX, et al.Alpha-lipoic acid upregulates SIRT1-dependent PGC-1alpha expression and protects mouse brain against focal ischemia. Neuroscience, 2014; 281:251–257; doi: 10.1016/j.neuroscience.2014.09.058
33.
FreireMAM, RochaGS, BittencourtLO, et al.Cellular and molecular pathophysiology of traumatic brain injury: What have we learned so far? Biology (Basel), 2023; 12(8):1139; doi: 10.3390/biology12081139
34.
BramlettHM, DietrichWD, GreenEJ, et al.Chronic histopathological consequences of fluid-percussion brain injury in rats: Effects of post-traumatic hypothermia. Acta Neuropathol, 1997; 93(2):190–199; doi: 10.1007/s004010050602
35.
ColicosMA, DixonCE, DashPK. Delayed, selective neuronal death following experimental cortical impact injury in rats: Possible role in memory deficits. Brain Res, 1996; 739(1–2):111–119; doi: 10.1016/s0006-8993(96)00819-0
36.
RocamondeB, ParadellsS, BarciaC, et al.Lipoic acid treatment after brain injury: Study of the glial reaction. Clin Dev Immunol, 2013; 2013:521939; doi: 10.1155/2013/521939
37.
AmlerovaZ, ChmelovaM, AnderovaM, et al.Reactive gliosis in traumatic brain injury: A comprehensive review. Front Cell Neurosci, 2024; 18:1335849; doi: 10.3389/fncel.2024.1335849
38.
TurtzoLC, LubyM, JikariaN, et al.Cytotoxic edema associated with hemorrhage predicts poor outcome after traumatic brain injury. J Neurotrauma, 2021; 38(22):3107–3118; doi: 10.1089/neu.2021.0037
39.
ShaoL, ChenS, MaL. Secondary brain injury by oxidative stress after cerebral hemorrhage: Recent advances. Front Cell Neurosci, 2022; 16:853589; doi: 10.3389/fncel.2022.853589
40.
StarkovAA. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci, 2008; 1147:37–52; doi: 10.1196/annals.1427.015
41.
SpikmanJM, TimmermanME, MildersMV, et al.Social cognition impairments in relation to general cognitive deficits, injury severity, and prefrontal lesions in traumatic brain injury patients. J Neurotrauma, 2012; 29(1):101–111; doi: 10.1089/neu.2011.2084
42.
DraperK, PonsfordJ. Cognitive functioning ten years following traumatic brain injury and rehabilitation. Neuropsychology, 2008; 22(5):618–625; doi: 10.1037/0894-4105.22.5.618
43.
WareJB, DoluiS, DudaJ, et al.Relationship of cerebral blood flow to cognitive function and recovery in early chronic traumatic brain injury. J Neurotrauma, 2020; 37(20):2180–2187; doi: 10.1089/neu.2020.7031
44.
KinnunenKM, GreenwoodR, PowellJH, et al.White matter damage and cognitive impairment after traumatic brain injury. Brain, 2011; 134(Pt 2):449–463; doi: 10.1093/brain/awq347
45.
BasileGA, IannuzzoF, XerraF, et al.Cognitive and mood effect of alpha-lipoic acid supplementation in a nonclinical elder sample: An open-label pilot study. Int J Environ Res Public Health, 2023; 20(3):2358; doi: 10.3390/ijerph20032358
46.
MemuduAE, AdanikeRP. Alpha lipoic acid reverses scopolamine-induced spatial memory loss and pyramidal cell neurodegeneration in the prefrontal cortex of Wistar rats. IBRO Neurosci Rep, 2022; 13:1–8; doi: 10.1016/j.ibneur.2022.05.005
47.
TanbekK, OzerolE, YilmazU, et al.Alpha lipoic acid decreases neuronal damage on brain tissue of STZ-induced diabetic rats. Physiol Behav, 2022; 248:113727; doi: 10.1016/j.physbeh.2022.113727
48.
ZhaoRR, XuF, XuXC, et al.Effects of alpha-lipoic acid on spatial learning and memory, oxidative stress, and central cholinergic system in a rat model of vascular dementia. Neurosci Lett, 2015; 587:113–119; doi: 10.1016/j.neulet.2014.12.037
49.
de FreitasRM. Lipoic Acid increases hippocampal choline acetyltransferase and acetylcholinesterase activities and improvement memory in epileptic rats. Neurochem Res, 2010; 35(1):162–170; doi: 10.1007/s11064-009-0041-6
50.
LalR, DharavathRN, ChopraK. Alpha-Lipoic acid ameliorates doxorubicin-induced cognitive impairments by modulating neuroinflammation and oxidative stress via NRF-2/HO-1 signaling pathway in the rat hippocampus. Neurochem Res, 2023; 48(8):2476–2489; doi: 10.1007/s11064-023-03914-y
51.
ZhangZG, WangX, ZaiJH, et al.Icariin improves cognitive impairment after traumatic brain injury by enhancing hippocampal acetylation. Chin J Integr Med, 2018; 24(5):366–371; doi: 10.1007/s11655-018-2823-z
52.
ArciniegasD, AdlerL, TopkoffJ, et al.Attention and memory dysfunction after traumatic brain injury: Cholinergic mechanisms, sensory gating, and a hypothesis for further investigation. Brain Inj, 1999; 13(1):1–13; doi: 10.1080/026990599121827
53.
ShinSS, DixonCE. Alterations in cholinergic pathways and therapeutic strategies targeting cholinergic system after traumatic brain injury. J Neurotrauma, 2015; 32(19):1429–1440; doi: 10.1089/neu.2014.3445
54.
ShaoW, WangJJ, NiuZH, et al.LFHP-1c improves cognitive function after TBI in mice by reducing oxidative stress through the PGAM5-NRF2-KEAP1 ternary complex. Heliyon, 2024; 10(17):e36820; doi: 10.1016/j.heliyon.2024.e36820
55.
Fesharaki-ZadehA. Oxidative stress in traumatic brain injury. Int J Mol Sci, 2022; 23(21):13000; doi: 10.3390/ijms232113000
56.
JiangM, SunL, FengDX, et al.Neuroprotection provided by isoflurane pre-conditioning and post-conditioning. Med Gas Res, 2017; 7(1):48–55; doi: 10.4103/2045-9912.202910
57.
StatlerKD, AlexanderH, VagniV, et al.Comparison of seven anesthetic agents on outcome after experimental traumatic brain injury in adult, male rats. J Neurotrauma, 2006; 23(1):97–108; doi: 10.1089/neu.2006.23.97
58.
StatlerKD, AlexanderH, VagniV, et al.Isoflurane exerts neuroprotective actions at or near the time of severe traumatic brain injury. Brain Res, 2006; 1076(1):216–224; doi: 10.1016/j.brainres.2005.12.106
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