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Lucke-Wold, B.; Aghili-Mehrizi, S.; , .; Willman, J. Emerging Treatments: Targeting Secondary Mechanisms of Neurotrauma. Encyclopedia. Available online: https://encyclopedia.pub/entry/23570 (accessed on 08 July 2025).
Lucke-Wold B, Aghili-Mehrizi S,  , Willman J. Emerging Treatments: Targeting Secondary Mechanisms of Neurotrauma. Encyclopedia. Available at: https://encyclopedia.pub/entry/23570. Accessed July 08, 2025.
Lucke-Wold, Brandon, Sina Aghili-Mehrizi,  , Jonathan Willman. "Emerging Treatments: Targeting Secondary Mechanisms of Neurotrauma" Encyclopedia, https://encyclopedia.pub/entry/23570 (accessed July 08, 2025).
Lucke-Wold, B., Aghili-Mehrizi, S., , ., & Willman, J. (2022, May 30). Emerging Treatments: Targeting Secondary Mechanisms of Neurotrauma. In Encyclopedia. https://encyclopedia.pub/entry/23570
Lucke-Wold, Brandon, et al. "Emerging Treatments: Targeting Secondary Mechanisms of Neurotrauma." Encyclopedia. Web. 30 May, 2022.
Emerging Treatments: Targeting Secondary Mechanisms of Neurotrauma
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This entry is adapted from the peer-reviewed paper 10.3390/diseases10020030

Traumatic central nervous system injury is a leading cause of neurological injury worldwide. While initial neuroresuscitative efforts are focused on ameliorating the effects of primary injury through patient stabilization, secondary injury in neurotrauma is a potential cause of cell death, oxidative stress, and neuroinflammation. These secondary injuries lack defined therapy. The major causes of secondary injury in neurotrauma include endoplasmic reticular stress, mitochondrial dysfunction, and the buildup of reactive oxygen or nitrogenous species. Stress to the endoplasmic reticulum in neurotrauma results in the overactivation of the unfolded protein response with subsequent cell apoptosis. Mitochondrial dysfunction can lead to the release of caspases and the buildup of reactive oxygen species; several characteristics make the central nervous system particularly susceptible to oxidative damage. Together, endoplasmic reticulum, mitochondrial, and oxidative stress can have detrimental consequences, beginning moments and lasting days to months after the primary injury. Understanding these causative pathways has led to the proposal of various potential treatment options.

neural injury oxidative stress endoplasmic reticulum stress apoptosis

1. ER Stress

Potential treatment options targeting the UPR pathway look to ameliorate ER stress as a cause of secondary injury in neurotrauma. Specifically, two drugs acting on eIF2α phosphorylation have shown promising results in recent studies on animal models. Salubrinal, an eIF2α dephoshorylation inhibitor, has recently been shown to decrease ER-stress-associated neuronal cell death via disrupting caspase-3-mediated apoptosis and neuroinflammation after TBI [1][2][3][4]. Similarly, Guanabenz and its derivatives (e.g., sephin1) have been shown to increase eIF2α phosphorylation [5][6]. Recent studies examining the therapeutic effect of Guanabenz and sephin1 have shown reductions in unfolded protein production, ER stress, and TBI neural deficits [7][8][9][10][11]. Additionally, Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, is another potential treatment targeting ER stress. Previous studies have shown TUDCA’s ability to promote blood vessel repair, reduce arterial stiffness, and decrease endothelial dysfunction in rodent models of type 2 diabetes [12][13]. However, recently, TUDCA use in rodent models of subarachnoid hemorrhage has been shown to increase cerebrovascular perfusion, decrease GRP78 expression, and inhibit PERK, eIF2α, and ATF4 signaling, ultimately decreasing ER-stress-mediated apoptosis [14].

2. Mitochondrial Dysfunction

A prominent cause of mitochondrial stress (and thus increased ROS formation) in neurotrauma is calcium overload via glutamate–NMDA interaction. While preliminary research focused on the broad-stroke downregulation of the NMDA receptor has proven to be counterproductive with many side effects and a limited window of therapy, research has shown that there are two NMDA receptors of interest: synaptic NMDA receptors which increase nuclear Ca2+ and antioxidant production and extra-synaptic NMDA receptors which promote cytoplasmic Ca2+ and mitochondrial stress [15]. Recent research has focused on the selective inhibition of extra-synaptic NMDA receptors via memantine, a well-studied neuroprotective drug in AD [16][17]. Preliminary studies in rodent models have shown that the memantine-mediated downregulation of extra-synaptic NMDA receptors in the setting of TBI is protective against mitochondrial stress and neuronal damage [16][17].
Another treatment option in mitochondrial dysfunction looks to inhibit mPTP formation by reproducing the effects of cyclosporin A (CsA). CsA has been well-documented in inhibiting apoptotic cell death in various cells, including neurons, presumably through its inhibition of the release of pro-apoptotic factors by mPTP [18][19][20]. However, its cytotoxic effects have limited CsA as a potential treatment option in neurotrauma [21][22]. NIM811, a cyclosporin A (CsA) analog, is a less toxic alternative currently under investigation, primarily for SCI [21]. In addition to preserving mitochondrial function, this potential treatment has been shown to promote tissue sparing and functional recovery in rodent models of SCI [21].

3. Antioxidant Therapy

Reactive species production is one of the more well-studied mechanisms of secondary injury in neurotrauma, and thus, a broader variety of potential treatment options targeting various pathways in their production and removal are currently under investigation. Edaravone is a multi-target compound that has been used in Japan since 2001 for its scavenging of free radicals post-ischemic stroke [23]. Recently, it was approved by the FDA for ALS treatment because of its ability to increase antioxidant enzyme expression and to prevent cyt c and caspase-3 release in the mitochondria [23]. Despite its use in ALS and stroke, there is limited studies on its safety and efficacy in TBI patients. In rodent models of TBI, edaravone has been shown to significantly reduce apoptotic activity in a dose-dependent fashion, with one study showing its benefits when administered up to 6 h following controlled cortical impact (CCI) [24]. Several other studies have shown decreased evidence of LP following edaravone administration as well as increased Nrf2 expression [24][25][26]. Another potential therapy that has shown promising results in rodent models of TBI is Apocynin/TBHQ. Apocynin, a NOX inhibitor, and TBHQ, a NRF2 activator, when used as a dual-blend therapy, can salvage both white and gray matter when administered up to 2 h after TBI [27]. Furthermore, Mitoquinone (MitoQ) is being investigated as an antioxidant that targets the mitochondrial ETC. Its actions on the mitochondria lead to a series of downstream effects that ultimately increase Nrf2 release and thus antioxidant enzyme gene expression [23][28]. Although its effects in PD, HD, AD, and ALS have been widely studied, the investigation of its benefits in TBI has only recently begun [28][29][30][31][32][33].

4. Immunoglobulin

Antibodies are a broad field of therapies that have garnered interest in the treatment of TBI partly due to their theoretically targeted nature. Kondo et al. demonstrated that TBI in mice induced cis phosphorylates-tau (p-tau) production, axonal interference, mitochondrial dysregulation, and subsequent apoptosis in a process they labeled “cistauosis” [34]. In addition, Kondo et al. showed that an anti-cis p-tau-specific antibody could rescue the majority of cistauosis-induced consequences, including apoptosis and mitochondrial dysfunction [34]. The concept that tau pathology is linked to mitochondrial dysregulation has been endorsed by studies from the field of Alzheimer’s research [35][36][37][38]. Kondo et al.’s findings and the possible use of a p-tau therapeutic antibody were subsequently supported by a number of recent studies [39][40][41]. One study of note demonstrated a statistically significant negative correlation between Glasgow Coma Scale results and cis p-tau levels in the CSF of human TBI patients [42]. This further endorses the notion that cis p-tau is directly associated with worse TBI results and that cis p-tau antibodies may have therapeutic value.
Another potential target of immunoglobulin therapy in TBI is the molecule caveolin. Increased caveolin-1 levels in the CSF have been associated with worse outcomes in TBI [43]. In addition, caveolin-1 mouse knockout was correlated with decreased inflammation and oxidative stress in the setting of TBI [44]. Caveolin-3, found largely in astrocytes within the CNS, is linked with a reduction in endothelial nitric oxide synthase (eNOS) [45][46][47]. This may promote oxidative injury, given the positive association between eNOS and reduced oxidative stress [48][49]. Further research in the field of caveolin modulation is vital before therapies may be developed.

5. Cell-Based Therapy

Stem-cell-based therapy for traumatic brain injury (TBI) has been a topic of research for many years and remains one of the foremost options as a future therapeutic. The divisions of stem cells used in TBI research include neural stem cells (NSCs), mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and multipotent adult progenitor cells (MAPCs) [50]. In recent years, research has focused more on the use of MSCs. MSCs have been shown to migrate to the cite of TBI, inhibit microglia activation and peripheral leukocyte migration, inhibit proinflammatory cytokines and oxidative stress, and repair injured tissue through the upregulation of growth factors (e.g., VEGF) and neurotrophic factor transcription (e.g., BDNF and GDNF) [50][51][52][53]. In addition, there is new evidence that MSCs may increase ATP production in the setting of ischemia through a process known as mitochondrial transfer, in which mitochondria are transferred from the MSC to local cells through a novel exocytotic process [54][55]. Two concerns regarding stem cell therapy in TBI include potential tumorgenicity and embolism formation [56][57]. While studies have repeatedly shown the increased risk of embolism formation in high-dose stem cell therapy, data have been inconclusive concerning the enhanced probability of tumorgenicity, with the latest studies finding no heightened risk [57][58].

6. MSC-Exosomes

In recent years, an innovative and focused application of TBI stem cell therapy called MSC-derived exosomes (MSC-exosomes) has emerged as a promising new therapy. Almost every cell in the human body exudes extracellular vesicles. There are two major categories of extracellular vesicles—ectosomes and exosomes, which are comparatively smaller with an average diameter of 100 nm [59]. MSC-exosomes contain many of the products of their parent MSC cells, including nucleic acids, lipids, and proteins [59][60]. In addition, research has shown that many of the benefits of MSCs are not based on the stem cells’ ability to differentiate and replace dead tissue, but rather on their ability upregulate growth factors and anti-inflammatory mediators that reduce oxidative stress and mitochondrial damage through exosome production and modulatory signaling [60][61][62][63]. Consequently, MSC-exosomes may offer many of the same advantages as MSCs without the cell-based risk factors [60][64]. Recent research has shown that MSC-exosomes may upregulate AKT and ERK pathways and counteract the effects of ER-stress-induced apoptosis while simultaneously downregulating genes associated with ER stress [65][66][67]. One study by Zhang et al. found that TBI rats treated with MSC-exosomes showed the significant rescue of neurological deficits, upregulation of endogenous angiogenesis, and reductions in lesion areas compared to a phosphate-buffered saline control group [68]. This finding of decreased lesion area was further supported by a subsequent study by Ni et al. [69]. A recent study examining the efficiency of delayed MSC-exosome therapy in TBI found that MSC-exosome administered to Yorkshire swine 9 h post-TBI still demonstrated a significant improvement in neurological recovery rates compared to a normal saline control group [70]. MSC-exosome therapy has also shown promise in modulating microglia activation and neuroinflammation. Several studies have found a significant reduction in microglia polarization and inflammation in MSC-exosome treatment of rodent TBI models [66][69][71].

7. CCR5 Antagonists

One of the most promising, novel targets of future TBI therapies may be CC chemokine receptor 5 (CCR5). CCR5 is a G-protein-coupled receptor that first gained recognition as an integral coreceptor in HIV cell infection but is now recognized as a significant player in the endogenous activation and trafficking of immune- and oxidative-stress-inducing cells, including macrophages and T cells [72][73][74][75]. There is also some evidence that CCR5 may interact with mitochondrial heat shock proteins expressed due to mitochondrial stress and contribute to cell apoptosis [76][77]. Accordingly, CCR5 inhibition has the potential to attenuate some of the effects of mitochondrial stress. A recent study by Haruwaka et al. demonstrated, with in vivo imaging during inflammation, that CCR5 performs an integral role in the trafficking of microglia to central nervous system vessels and, consequently, may induce permeability and failure of integrity in the blood–brain barrier (BBB) [78]. These findings indicate that CCR5 may play a role in microglia activation and ROS response post-TBI. Furthermore, there is evidence that CCR5 transcription is upregulated for 7 days following a TBI [79]. This suggests that CCR5 may have a lasting effect post-TBI. Several studies examining TBI outcomes in CCR5 knockout or silenced rodents compared to WT have consistently demonstrated improved neurological outcomes, reduced fields of damage, and earlier recovery [80][81][82]. Joy et al. examined outcomes from the Tel Aviv Brain Acute Stroke Cohort study and were able to demonstrate a significant correlation between better stroke outcomes amongst enrollees with a CCR5 loss of function mutation compared to those with CCR5 WT [80]. Potential CCR5 antagonistic therapeutics already FDA-approved for HIV treatment include Cenicriviroc and Maraviroc. Consequently, studies have already demonstrated the effectiveness of Maraviroc as a CCR5 antagonist in rodents with TBI, with outcomes paralleling those found in the knockout studies [80][82].

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Subjects: Neurosciences
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Brandon Lucke-Wold
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Sina Aghili-Mehrizi
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Jonathan Willman
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Update Date: 31 May 2022
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