Memantine Mitigates Oligodendrocyte Damage after Repetitive Mild Traumatic Brain Injury

Ma, Guixian; Liu, Changyun; Hashim, Jumana; Conley, Grace; Morriss, Nicholas; Meehan, William P.; Qiu, Jianhua; Mannix, Rebekah

doi:10.1016/j.neuroscience.2019.10.016

Cited by 16 publications

(10 citation statements)

References 70 publications

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“…The treatment of memantine, a low-affinity uncompetitive NMDAR antagonist without affecting normal physiological activity, attenuated anesthesia and surgery-induced overactivation of NMDARs and calpain and improved cognitive impairments in aging mice. It has been previously demonstrated that memantine is neuroprotective in various brain diseases, including AD [40], Parkinson's disease [41], traumatic brain injury [42], and paininduced cognitive impairments [43], which involves its anti-inflammation, anti-oxidation, anti-apoptosis, and anti-glutamate excitotoxicity properties. In our study, we showed that NMDAR/Ca 2+ /calpain is mechanistically involved in neuroprotective effects of memantine in anesthesia and surgery-induced cognitive impairments in aging mice.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Qiu

Pan

Luo

et al. 2020

J Neuroinflammation

166

117

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Background: Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca 2+ -dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca 2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca 2+ /calpain might be involved in the pathogenesis of POCD.Methods: In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus.Results: Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment. Conclusion: Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Qiu

Pan

Luo

et al. 2020

J Neuroinflammation

166

117

View full text Add to dashboard Cite

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“…A study focusing on comorbid blast-induced mTBI used BCI-838 (MSGS0210), a Group II metabotropic glutamate receptor (mGluR2/3) antagonist (BCI-838), which reduced PTSD-like behavior, anxiety, fearful behavior, and long-term recognition memory impairment (104). Memantine remains among treatment options, exhibiting a potential to mitigate neuropathological and behavioral outcomes in mTBI and lessen PTSD-like behavior (137)(138)(139)(140). As no FDA-approved treatments for TBI exist, this article provides a preview of opportunities for therapeutic research using preclinical modeling platforms.…”

Section: Biomarker Development and Treatment Approaches For Blast-ind...mentioning

confidence: 99%

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

et al. 2022

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Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

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“…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 Ca 2+ and antioxidant production and extra-synaptic NMDA receptors which promote cytoplasmic Ca 2+ and mitochondrial stress [ 93 ]. Recent research has focused on the selective inhibition of extra-synaptic NMDA receptors via memantine, a well-studied neuroprotective drug in AD [ 80 , 94 ].…”

Section: Emerging Treatmentsmentioning

confidence: 99%

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence

et al. 2022

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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.

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Memantine Mitigates Oligodendrocyte Damage after Repetitive Mild Traumatic Brain Injury

Cited by 16 publications

References 70 publications

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence

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