The post‐therapeutic effect of rapamycin in mild traumatic brain‐injured rats ensuing in the upregulation of autophagy and mitophagy

Wang, Changxing; Hu, Zhiying; Zou, Yang; Xiang, Mingjun; Jiang, Yuting; Botchway, Benson O. A.; Huo, Xue; Du, Xiaoxue; Fang, Marong

doi:10.1002/cbin.10820

Cited by 31 publications

(19 citation statements)

References 37 publications

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“…Likewise, in individuals with CTE symptoms, similar phenotypic manifestations have been reported as the condition progresses (Omalu et al, ). Results from the studies assessed here indicate increased anxiety and impaired attention (Hehar, Yeates, Kolb, Esser, & Mychasiuk, ; Wang et al, ; Yamakawa, Salberg, et al, ). There was also a consistent depression‐like response to the forced swim task in mTBI groups, as evidenced by immobility and disinclination to swim (Salberg et al, ).…”

Section: Discussionmentioning

confidence: 69%

Modeling sports‐related mild traumatic brain injury in animals—A systematic review

Hiskens

Angoa‐Pérez

Schneiders

et al. 2019

J of Neuroscience Research

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Sports-related head trauma has emerged as an important public health issue, as mild traumatic brain injuries (mTBIs) may result in neurodegenerative disorders such as chronic traumatic encephalopathy (CTE). Research into mTBI and CTE pathophysiology are difficult to undertake in athletes, with observational trials and post-mortem analysis the current mainstays. Thus, animal models play an important role in the study of mTBI, however, traditional animal models have focused on acute, severe injuries rather than the more typical mTBI's seen in sport injuries. Recently, a number of animal models have been developed that are both appropriately scaled and biomechanically relevant to the forces sustained by athletes. This review aimed to examine the literature for variables included in these animal models, and the resulting neurotrauma as evidenced by pathology and behavioral deficits. A systematic search of the literature was performed in multiple electronic databases. The inclusion criteria required mimicry of athlete mTBI conditions: freedom of head movement, lack of surgical alteration of the skull, and application of direct contact force. Studies were analyzed for variables including apparatus design features (impact force, change in animal head velocity, and kinetic energy transfer to the head), demonstrated pathology (phosphorylated tau, TDP-43 aggregation, diffuse axonal injury, gliosis, cytokine inflammation response, and genetic integrity), and behavioral changes. These studies suggested that appropriate animal models can assist in understanding the pathological and functional outcomes of athlete mTBI, and could be used as a platform for future studies of diagnostic/prognostic markers and in the development of treatment interventions. K E Y W O R D S animal models, chronic traumatic encephalopathy, concussion, neurotrauma | INTRODUC TI ONAthlete head impacts continue to attract significant media and research attention with sports such as soccer, football, ice hockey, lacrosse, and rugby displaying significant rates of head injury in American high school and collegiate athletes O'Connor et al., 2017). These impacts occur across a continuum of severity; from injuries resulting in unconsciousness and requiring the athlete to be assisted on the field, to contact with no immediate observable consequences, such as heading a soccer ball. The nature of many of these sports predicates that head impacts are not sustained in isolation, but are often an intrinsic by-product of the rules of the sport, and as such are repetitively sustained across a match | 1195 HISKENS Et al.

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Section: Discussionmentioning

confidence: 69%

Modeling sports‐related mild traumatic brain injury in animals—A systematic review

Hiskens

Angoa‐Pérez

Schneiders

et al. 2019

J of Neuroscience Research

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“…Within this context autophagy of mitochondria might play an important positive homeostatic role of in endogenous metabolic rebalancing in acute injury, especially in TBI (Smith et al, 2011). In line with this, the induction of autophagy using rapamycin inhibited an important mitochondrial cell death pathway with decreased cyt c release and caspase 3 activation (Tang et al, 2016;Wang et al, 2017;Wu et al, 2017), while inhibition of mitophagy by mdivi-1-induced cyt c release and caspase 3 activa- Figure 8. PLS3 knockdown exacerbates neuronal injury and behavioral deficits after TBI.…”

Section: Discussionmentioning

confidence: 81%

“…V, Vehicle. et al, 2016;Liu et al, 2017b;Wang et al, 2017;Wu et al, 2017). A number of studies have reported presence of abnormal mitochondria early after acute injury, possibly associated with energy depletion and/or disturbed Ca 2ϩ homeostasis (Cheng et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…There are several limitations to our study. First being focused on the involvement of CL in the mitophageal elimination of damaged mitochondria, this study did not explore the possible contribution of PINK1/Parkin (Mukhida et al, 2005;Zhang et al, 2013;Wang et al, 2017) to TBI-induced mitophagy in the brain. Second, we used a developmental TBI model in juvenile rats whereas the clinical samples were obtained from adult patients.…”

Section: Discussionmentioning

confidence: 99%

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Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury

Chao

Lin²,

Zuo

et al. 2019

J. Neurosci.

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Mitochondrial energy production is essential for normal brain function. Traumatic brain injury (TBI) increases brain energy demands, results in the activation of mitochondrial respiration, associated with enhanced generation of reactive oxygen species. This chain of events triggers neuronal apoptosis via oxidation of a mitochondria-specific phospholipid, cardiolipin (CL). One pathway through which cells can avoid apoptosis is via elimination of damaged mitochondria by mitophagy. Previously, we showed that externalization of CL to the mitochondrial surface acts as an elimination signal in cells. Whether CL-mediated mitophagy occurs in vivo or its significance in the disease processes are not known. In this study, we showed that TBI leads to increased mitophagy in the human brain, which was also detected using TBI models in male rats. Knockdown of CL synthase, responsible for de novo synthesis of CL, or phospholipid scramblase-3, responsible for CL translocation to the outer mitochondrial membrane, significantly decreased TBI-induced mitophagy. Inhibition of mitochondrial clearance by 3-methyladenine, mdivi-1, or phospholipid scramblase-3 knockdown after TBI led to a worse outcome, suggesting that mitophagy is beneficial. Together, our findings indicate that TBI-induced mitophagy is an endogenous neuroprotective process that is directed by CL, which marks damaged mitochondria for elimination, thereby limiting neuronal death and behavioral deficits.

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“…More generally, rapamycin has demonstrated beneficial effects in the context of acute CNS damage showing increased neuronal survival after spinal cord or brain injury as well as RGC rescue after optic nerve transection and ischaemia/reperfusion 36,56 . Rapamycin is well known to increase autophagy, and also upregulates mitophagy and mitochondrial fission in in vivo CNS damage models [73][74][75][76] . Supporting possible increase of mitophagy after ONC, EM pictures of RGCs after optic nerve transection show increased numbers of mitochondria in autolysosomes 6 days after the insult 36 .…”

Section: Discussionmentioning

confidence: 99%

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

et al. 2020

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Glaucoma is a common age-related disease leading to progressive retinal ganglion cell (RGC) death, visual field defects and vision loss and is the second leading cause of blindness in the elderly worldwide. Mitochondrial dysfunction and impaired autophagy have been linked to glaucoma and induction of autophagy shows neuroprotective effects in glaucoma animal models. We have shown that autophagy decreases with aging in the retina and that autophagy can be neuroprotective for RGCs, but it is currently unknown how aging and autophagy deficiency impact RGCs susceptibility and survival. Using the optic nerve crush model in young and olWelcome@1234d Ambra1 +/gt (autophagy/beclin-1 regulator 1 +/gt) mice we analysed the contribution of autophagy deficiency on retinal ganglion cell survival in an age dependent context. Interestingly, old Ambra1 +/gt mice showed decreased RGC survival after optic nerve crush in comparison to old Ambra1 +/+ , an effect that was not observed in the young animals. Proteomics and mRNA expression data point towards altered oxidative stress response and mitochondrial alterations in old Ambra1 +/gt animals. This effect is intensified after RGC axonal damage, resulting in reduced oxidative stress response showing decreased levels of Nqo1, as well as failure of Nrf2 induction in the old Ambra1 +/gt. Old Ambra1 +/gt also failed to show increase in Bnip3l and Bnip3 expression after optic nerve crush, a response that is found in the Ambra1 +/+ controls. Primary RGCs derived from Ambra1 +/gt mice show decreased neurite projection and increased levels of apoptosis in comparison to Ambra1 +/+ animals. Our results lead to the conclusion that oxidative stress response pathways are altered in old Ambra1 +/gt mice leading to impaired damage responses upon additional external stress factors.

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The post‐therapeutic effect of rapamycin in mild traumatic brain‐injured rats ensuing in the upregulation of autophagy and mitophagy

Cited by 31 publications

References 37 publications

Modeling sports‐related mild traumatic brain injury in animals—A systematic review

Modeling sports‐related mild traumatic brain injury in animals—A systematic review

Cardiolipin-Dependent Mitophagy Guides Outcome after Traumatic Brain Injury

Age related retinal Ganglion cell susceptibility in context of autophagy deficiency

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