Cyclosporin A preserves mitochondrial function after traumatic brain injury in the immature rat and piglet
Todd J Kilbaugh1, Sunita Bhandare, David H Lorom
1University of Pennsylvania School of Medicine, Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Insights
Cyclosporin A (CsA) protects immature brains from traumatic brain injury (TBI) by preserving mitochondrial function and blood flow. This neuroprotective effect was observed in both focal and diffuse TBI models, suggesting potential therapeutic use in children.
Area of Science:
- Neuroscience
- Pharmacology
- Pediatric Traumatology
Background:
- Cyclosporin A (CsA) demonstrates neuroprotection in mature traumatic brain injury (TBI) models by inhibiting the mitochondrial permeability transition pore (MPTP).
- The neuroprotective effects of CsA in immature TBI models remain uninvestigated.
- Understanding CsA's impact on mitochondrial homeostasis and cerebral hemodynamics in developing brains is crucial.
Purpose of the Study:
- To evaluate the neuroprotective efficacy of Cyclosporin A (CsA) in immature animal models of focal and diffuse traumatic brain injury (TBI).
- To assess CsA's ability to preserve mitochondrial bioenergetic function and cerebral blood flow (CBF) post-TBI in immature rats and piglets.
- To investigate CsA's impact on neuropathology and brain volume following TBI in immature models.
Main Methods:
- Immature rats and piglets were subjected to controlled cortical impact (CCI) or rapid non-impact rotational injury (RNR), respectively.
- Groups included: injured+CsA, injured+saline vehicle, and uninjured shams.
- Mitochondrial respiration, cerebral microdialysis (lactate pyruvate ratio - LPR), cerebral blood flow (CBF) using thermal diffusion, and injured brain volume were assessed 24 hours post-TBI.
Main Results:
- Post-injury CsA administration ameliorated mitochondrial dysfunction, preserving the respiratory control ratio (RCR) to sham levels in both rat and piglet models.
- CsA significantly preserved cerebral blood flow (CBF) and lactate pyruvate ratios (LPR) in piglets, unlike in untreated injured piglets.
- CsA treatment reduced injured brain volume by 42% in piglets following RNR (p<0.01).
Conclusions:
- Cyclosporin A (CsA) exhibits significant neuroprotective activity in immature models of both focal and diffuse traumatic brain injury (TBI).
- CsA preserves mitochondrial bioenergetic function, cerebral blood flow, and limits neuropathology in developing brains post-TBI.
- CsA holds considerable translational potential as a therapeutic agent for neuroprotection in pediatric TBI.
Abstract:
Cyclosporin A (CsA) has been shown to be neuroprotective in mature animal models of traumatic brain injury (TBI), but its effects on immature animal models of TBI are unknown. In mature animal models, CsA inhibits the opening of the mitochondrial permeability transition pore (MPTP), thereby maintaining mitochondrial homeostasis following injury by inhibiting calcium influx and preserving mitochondrial membrane potential. The aim of the present study was to evaluate CsA's ability to preserve mitochondrial bioenergetic function following TBI (as measured by mitochondrial respiration and cerebral microdialysis), in two immature models (focal and diffuse), and in two different species (rat and piglet). Three groups were studied: injured+CsA, injured+saline vehicle, and uninjured shams. In addition, we evaluated CsA's effects on cerebral hemodynamics as measured by a novel thermal diffusion probe. The results demonstrate that post-injury administration of CsA ameliorates mitochondrial dysfunction, preserves cerebral blood flow (CBF), and limits neuropathology in immature animals 24 h post-TBI. Mitochondria were isolated 24 h after controlled cortical impact (CCI) in rats and rapid non-impact rotational injury (RNR) in piglets, and CsA ameliorated cerebral bioenergetic crisis with preservation of the respiratory control ratio (RCR) to sham levels. Results were more dramatic in RNR piglets than in CCI rats. In piglets, CsA also preserved lactate pyruvate ratios (LPR), as measured by cerebral microdialysis and CBF at sham levels 24 h after injury, in contrast to the significant alterations seen in injured piglets compared to shams (p<0.01). The administration of CsA to piglets following RNR promoted a 42% decrease in injured brain volume (p<0.01). We conclude that CsA exhibits significant neuroprotective activity in immature models of focal and diffuse TBI, and has exciting translational potential as a therapeutic agent for neuroprotection in children.
More Related Videos
06:50A Preclinical Controlled Cortical Impact Model for Traumatic Hemorrhage Contusion and Neuroinflammation
Published on: June 10, 2020
09:29Controlled Cortical Impact Model of Mouse Brain Injury with Therapeutic Transplantation of Human Induced Pluripotent Stem Cell-Derived Neural Cells
Published on: July 10, 2019