Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury

van Hameren, Gerben; Muradov, Jamil; Minarik, Anna; Aboghazleh, Refat; Orr, Sophie; Cort, Shayna; Andrews, Keiran; McKenna, Caitlin; Pham, Nga Thy; MacLean, Mark A.; Friedman, Alon

doi:10.1016/j.nbd.2023.106269

Cited by 9 publications

(4 citation statements)

References 71 publications

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“…Finally, we acknowledge that the beneficial neurobehavioral effect observed in our trial of memantine for rmTBI could be independent of an effect on CSD. However, we have recently shown that spontaneously occurring CSD following TBI and electrically triggered CSD in sham animals are both associated with decline in neurobehavioral function ( 70 ).…”

Section: Discussionmentioning

confidence: 99%

“…A modified Marmarou weight-drop model was used to induce either a single mild (500 g mass, 85 cm height; mild TBI) or moderate (450 g mass, 1.02 m height; modTBI) head impact ( 5 , 70 , 81 , 82 ). Impacts were delivered anterior to the lambda suture line and posterior to bregma.…”

Section: Methodsmentioning

confidence: 99%

“…Mortality was rare, and both brain magnetic resonance imaging and gross post-mortem pathological assessment revealed no intracranial bleeding or structural injury ( 5 ). Twenty minutes following modTBI, behavioral scores were reduced and followed a normal distribution ( 70 ). Forty-eight hours following modTBI, behavioral scores remained reduced, and the distribution was bimodal.…”

Section: Methodsmentioning

confidence: 99%

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Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury

MacLean,

Muradov,

Greene

et al. 2023

Sci. Adv.

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Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals ( N = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury

MacLean,

Muradov,

Greene

et al. 2023

Sci. Adv.

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“…Cellular oxygen deficiency hampers the mitochondrial electron transport chain, restricting or stopping mitochondrial oxidative phosphorylation. This leads to the accumulation of excess oxygen radicals, contributing to oxidative stress and further triggering CSD ( 44 ). Research has linked migraine to mitochondrial dysfunction, evidenced by reduced mitochondrial membrane potential and the dysregulated activity of mitochondrial permeability transition pores.…”

Section: Neuroinflammation In Migrainementioning

confidence: 99%

Neuroimmunological effects of omega-3 fatty acids on migraine: a review

Chen,

Yang,

Tsai

et al. 2024

Front. Neurol.

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Migraine is a highly prevalent disease worldwide, imposing enormous clinical and economic burdens on individuals and societies. Current treatments exhibit limited efficacy and acceptability, highlighting the need for more effective and safety prophylactic approaches, including the use of nutraceuticals for migraine treatment. Migraine involves interactions within the central and peripheral nervous systems, with significant activation and sensitization of the trigeminovascular system (TVS) in pain generation and transmission. The condition is influenced by genetic predispositions and environmental factors, leading to altered sensory processing. The neuroinflammatory response is increasingly recognized as a key event underpinning the pathophysiology of migraine, involving a complex neuro-glio-vascular interplay. This interplay is partially mediated by neuropeptides such as calcitonin gene receptor peptide (CGRP), pituitary adenylate cyclase activating polypeptide (PACAP) and/or cortical spreading depression (CSD) and involves oxidative stress, mitochondrial dysfunction, nucleotide-binding domain-like receptor family pyrin domain containing-3 (NLRP3) inflammasome formation, activated microglia, and reactive astrocytes. Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), crucial for the nervous system, mediate various physiological functions. Omega-3 PUFAs offer cardiovascular, neurological, and psychiatric benefits due to their potent anti-inflammatory, anti-nociceptive, antioxidant, and neuromodulatory properties, which modulate neuroinflammation, neurogenic inflammation, pain transmission, enhance mitochondrial stability, and mood regulation. Moreover, specialized pro-resolving mediators (SPMs), a class of PUFA-derived lipid mediators, regulate pro-inflammatory and resolution pathways, playing significant anti-inflammatory and neurological roles, which in turn may be beneficial in alleviating the symptomatology of migraine. Omega-3 PUFAs impact various neurobiological pathways and have demonstrated a lack of major adverse events, underscoring their multifaceted approach and safety in migraine management. Although not all omega-3 PUFAs trials have shown beneficial in reducing the symptomatology of migraine, further research is needed to fully establish their clinical efficacy and understand the precise molecular mechanisms underlying the effects of omega-3 PUFAs and PUFA-derived lipid mediators, SPMs on migraine pathophysiology and progression. This review highlights their potential in modulating brain functions, such as neuroimmunological effects, and suggests their promise as candidates for effective migraine prophylaxis.

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Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction

Pang,

Dong,

Pang

et al. 2024

Angiogenesis

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As a vital component of blood vessels, endothelial cells play a key role in maintaining overall physiological function by residing between circulating blood and semi-solid tissue. Various stress stimuli can induce endothelial injury, leading to the onset of corresponding diseases in the body. In recent years, the importance of mitochondria in vascular endothelial injury has become increasingly apparent. Mitochondria, as the primary site of cellular aerobic respiration and the organelle for “energy information transfer,” can detect endothelial cell damage by integrating and receiving various external stress signals. The generation of reactive oxygen species (ROS) and mitochondrial dysfunction often determine the evolution of endothelial cell injury towards necrosis or apoptosis. Therefore, mitochondria are closely associated with endothelial cell function, helping to determine the progression of clinical diseases. This article comprehensively reviews the interconnection and pathogenesis of mitochondrial-induced vascular endothelial cell injury in cardiovascular diseases, renal diseases, pulmonary-related diseases, cerebrovascular diseases, and microvascular diseases associated with diabetes. Corresponding therapeutic approaches are also provided. Additionally, strategies for using clinical drugs to treat vascular endothelial injury-based diseases are discussed, aiming to offer new insights and treatment options for the clinical diagnosis of related vascular injuries.

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Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury

Cited by 9 publications

References 71 publications

Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury

Memantine inhibits cortical spreading depolarization and improves neurovascular function following repetitive traumatic brain injury

Neuroimmunological effects of omega-3 fatty acids on migraine: a review

Emerging insights into the pathogenesis and therapeutic strategies for vascular endothelial injury-associated diseases: focus on mitochondrial dysfunction

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