Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog

Earlier experiments have shown that cyclosporin A (CsA) and its non-calcineurin inhibitory analog NIM811 attenuate mitochondrial dysfunction after experimental traumatic brain injury (TBI). Presently, we compared the neuroprotective effects of previously determined mitochondrial protective doses of CsA (20 mg/kg intraperitoneally) and NIM811 (10 mg/kg intraperitoneally) when administered at 15 mins postinjury in preventing cytoskeletal (α-spectrin) degradation, neuro-degeneration, and neurological dysfunction after severe (1.0 mm) controlled cortical impact (CCI) TBI in mice. In a first set of experiments, we analyzed calpain-mediated α-spectrin proteolysis at 24 h postinjury. Both NIM811 and CsA significantly attenuated the increased α-spectrin breakdown products observed in vehicle-treated animals ( P < 0.005). In a second set of experiments, treatment of animals with either NIM811 or CsA at 15 mins and again at 24 h postinjury attenuated motor function impairment at 48 h and 7 days ( P < 0.005) and neurodegeneration at 7 days postinjury ( P < 0.0001). Delayed administration of NIM811 out to 12 h was still able to significantly reduce α-spectrin degradation. These results show that the neuroprotective mechanism of CsA involves maintenance of mitochondrial integrity and that calcineurin inhibition plays little or no role because the non-calcineurin inhibitory analog, NIM811, is as effective as CsA.

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The Protective Effect of Cyclosporin A upon N-Acetylaspartate and Mitochondrial Dysfunction following Experimental Diffuse Traumatic Brain Injury

Journal of Neurotrauma ◽

10.1089/neu.2004.21.1154 ◽

2004 ◽

Vol 21 (9) ◽

pp. 1154-1167 ◽

Cited By ~ 56

Author(s):

Stefano Signoretti ◽

Anthony Marmarou ◽

Barbara Tavazzi ◽

Jana Dunbar ◽

Angela M. Amorini ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Protective Effect ◽

Cyclosporin A ◽

Mitochondrial Dysfunction

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Cyclosporin A Attenuates Acute Mitochondrial Dysfunction Following Traumatic Brain Injury

Experimental Neurology ◽

10.1006/exnr.1999.7197 ◽

1999 ◽

Vol 160 (1) ◽

pp. 226-234 ◽

Cited By ~ 251

Author(s):

Patrick G. Sullivan ◽

Michael B. Thompson ◽

Stephen W. Scheff

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cyclosporin A ◽

Mitochondrial Dysfunction

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The Protective Effect of Cyclosporin A upon N-Acetylaspartate and Mitochondrial Dysfunction following Experimental Diffuse Traumatic Brain Injury

Journal of Neurotrauma ◽

10.1089/0897715041953885 ◽

2004 ◽

Vol 21 (9) ◽

pp. 1154-1167

Author(s):

Stefano Signoretti ◽

Anthony Marmarou ◽

Barbara Tavazzi ◽

Jana Dunbar ◽

Angela M. Amorini ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Protective Effect ◽

Cyclosporin A ◽

Mitochondrial Dysfunction

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Oxidative Stress: Major Threat in Traumatic Brain Injury

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180627120501 ◽

2018 ◽

Vol 17 (9) ◽

pp. 689-695 ◽

Cited By ~ 37

Author(s):

Nidhi Khatri ◽

Manisha Thakur ◽

Vikas Pareek ◽

Sandeep Kumar ◽

Sunil Sharma ◽

...

Keyword(s):

Oxidative Stress ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Mitochondrial Dysfunction ◽

Calcium Influx ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Physical Assault ◽

Mortality And Morbidity ◽

Primary Injury

Background & Objective: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies. Conclusion: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.

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