Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury

Wu, Qiong; Xia, S. X.; Li, Qianqian; Gao, Yuan; Shen, Xiaoye; Ma, Lu; Zhang, Mingyang; Wang, Tao; Li, Yongsheng; Wang, Zufeng; Luo, Chengliang; Tao, Luyang

doi:10.1016/j.brainres.2015.11.016

Cited by 90 publications

(55 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41 Inhibition of Drp1 by Mdivi-1 was also shown to improve hippocampal-dependent learning and memory and decrease lesion volume in mice and rats following TBI. 20,47 Taken together, these studies strongly suggest that Drp1 plays an important role in regulating neuronal death during CNS insults.…”

mentioning

confidence: 72%

“…5,8,40 Once recruited to mitochondria, Drp1 forms spiral tubules at the OMM and constrict the mitochondria using its intrinsic GTPase activity. 4,29 Mdivi-1 is a BBB permeable inhibitor of Drp1 that when injected systemically achieves maximum concentration in the brain by 4 h, and has a half-life of about 12 h. 41,18,20,30,[41][42][43][44][45][46][47] Blocking Drp1 by Mdivi-1 could restore mitochondrial dynamics, improve mitochondrial function by preserving mitochondrial structural integrity, and mÉ and ATP levels. 41 Treatment with Mdivi was shown to significantly decrease the infarct volume, apoptotic neuronal death and neurological deficits following transient middle cerebral artery occlusion (MCAO) in adult mice and rats.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial fission and fusion in secondary brain damage after CNS insults

Balog

Mehta

Vemuganti

2016

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Mitochondria are dynamically active organelles, regulated through fission and fusion events to continuously redistribute them across axons, dendrites, and synapses of neurons to meet bioenergetics requirements and to control various functions, including cell proliferation, calcium buffering, neurotransmission, oxidative stress, and apoptosis. However, following acute or chronic injury to CNS, altered expression and function of proteins that mediate fission and fusion lead to mitochondrial dynamic imbalance. Particularly, if the fission is abnormally increased through pro-fission mediators such as Drp1, mitochondrial function will be impaired and mitochondria will become susceptible to insertion of proapototic proteins. This leads to the formation of mitochondrial transition pore, which eventually triggers apoptosis. Thus, mitochondrial dysfunction is a major promoter of neuronal death and secondary brain damage after an insult. This review discusses the implications of mitochondrial dynamic imbalance in neuronal death after acute and chronic CNS insults.

show abstract

mentioning

confidence: 72%

mentioning

confidence: 99%

Mitochondrial fission and fusion in secondary brain damage after CNS insults

Balog

Mehta

Vemuganti

2016

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…2), a selective Drp1 inhibitor, has proven beneficial in in vivo models of various CNS and non-CNS pathologies, including TBI (Wu et al, 2016), amyotrophic lateral sclerosis (Luo et al, 2013), stroke (Zhang et al, 2013;Cui et al, 2016), acute kidney injury (Tang et al, 2013), and myocardial infarction (Ding et al, 2017). Despite these data, only two studies thus far have investigated the effect of Mdivi-1 on SCI Liu et al, 2015).…”

Section: Mitochondrial-based Treatmentmentioning

confidence: 99%

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target

Scholpa

Schnellmann

2017

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Spinal cord injury (SCI) is characterized by an initial trauma followed by a progressive cascade of damage referred to as secondary injury. A hallmark of secondary injury is vascular disruption leading to vasoconstriction and decreased oxygen delivery, which directly reduces the ability of mitochondria to maintain homeostasis and leads to loss of ATP-dependent cellular functions, calcium overload, excitotoxicity, and oxidative stress, further exacerbating injury. Restoration of mitochondria dysfunction during the acute phases of secondary injury after SCI represents a potentially effective therapeutic strategy. This review discusses the past and present pharmacological options for the treatment of SCI as well as current research on mitochondria-targeted approaches. Increased antioxidant activity, inhibition of the mitochondrial permeability transition, alternate energy sources, and manipulation of mitochondrial morphology are among the strategies under investigation. Unfortunately, many of these tactics address single aspects of mitochondrial dysfunction, ultimately proving largely ineffective. Therefore, this review also examines the unexplored therapeutic efficacy of pharmacological enhancement of mitochondrial biogenesis, which has the potential to more comprehensively improve mitochondrial function after SCI.

show abstract

“…In cultured neurons Drp1 ablation leads to a super-elongation of the mitochondrial network and has been shown to be neuroprotective [11]. Accordingly, several studies reported neuroprotective effects of Drp1 inhibitors in animal models of brain ischemia [12][13][14][15], retinal ganglion cell ischemia [16], spinal cord ischemia and injury [17,18], traumatic brain injury [19], status epilepticus [20][21][22], as well as Huntington's [23] and Parkinson's disease (PD) [24]. However, seemingly contradictory in vitro studies of Drp1 ablation in cultured neurons have also reported the formation of spherically enlarged mitochondria that aggregate in the perikarya.…”

Section: Commentarymentioning

confidence: 99%

Lessons Learned from Transgenic Mouse Models for the Therapeutic Use of Drp1 Inhibitors

Licci¹,

Björn²

2016

Single Cell Biol

View full text Add to dashboard Cite

Pharmacological inhibition of dynamin-related protein 1 (Drp1) the main mammalian promoter of mitochondrial fission -has emerged as a promising therapeutic target for the treatment of neuronal injuries. Genetic studies, however, have revealed that inhibiting Drp1 during development leads to defects especially in neuronal differentiation. Bypassing this neurodevelopmental impairment, a number of recent studies have genetically ablated Drp1 in different adult neuronal subpopulations. This has led to new insights into the importance of mitochondrial fission in differentiated neurons and has highlighted potentially severe side effects of this new therapeutic strategy.

show abstract

Mitochondrial division inhibitor 1 (Mdivi-1) offers neuroprotection through diminishing cell death and improving functional outcome in a mouse model of traumatic brain injury

Cited by 90 publications

References 35 publications

Mitochondrial fission and fusion in secondary brain damage after CNS insults

Mitochondrial fission and fusion in secondary brain damage after CNS insults

Mitochondrial-Based Therapeutics for the Treatment of Spinal Cord Injury: Mitochondrial Biogenesis as a Potential Pharmacological Target

Lessons Learned from Transgenic Mouse Models for the Therapeutic Use of Drp1 Inhibitors

Contact Info

Product

Resources

About