Neuroprotective Effects of Cyclosporine in a Porcine Pre-Clinical Trial of Focal Traumatic Brain Injury

Karlsson, Michael; Pukenas, Bryan; Chawla, Sanjeev; Ehinger, Johannes K.; Plyler, Ross; Stolow, Madeline; Gabello, Melissa; Hugerth, Matilda; Elmér, Eskil; Hansson, Magnus; Margulies, Susan S.; Kilbaugh, Todd J.

doi:10.1089/neu.2018.5706

Cited by 33 publications

(21 citation statements)

References 85 publications

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“…In contrast, the glucose-lowering compound Imeglimine, though to date only tested experimentally, has none of the side effects as metformin, but inhibited mitochondrial permeability transition, improved mitochondrial function, and was associated with less acidosis ( 100 , 101 ). The inhibition of the mitochondrial permeability transition pore with cyclosporine A showed promise in a pre-clinical sepsis model and a large-animal model of traumatic brain injury ( 102 , 103 ). In humans, cyclosporine A did not show a benefit in cardiac arrest and acute myocardial infarct ( 104 , 105 ), and it was never clinically approved for the treatment of any type of circulatory shock.…”

Section: Does “Mitochondrial Resuscitation” Help?mentioning

confidence: 99%

Microcirculation vs. Mitochondria—What to Target?

et al. 2020

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Circulatory shock is associated with marked disturbances of the macro- and microcirculation and flow heterogeneities. Furthermore, a lack of tissue adenosine trisphosphate (ATP) and mitochondrial dysfunction are directly associated with organ failure and poor patient outcome. While it remains unclear if microcirculation-targeted resuscitation strategies can even abolish shock-induced flow heterogeneity, mitochondrial dysfunction and subsequently diminished ATP production could still lead to organ dysfunction and failure even if microcirculatory function is restored or maintained. Preserved mitochondrial function is clearly associated with better patient outcome. This review elucidates the role of the microcirculation and mitochondria during circulatory shock and patient management and will give a viewpoint on the advantages and disadvantages of tailoring resuscitation to microvascular or mitochondrial targets.

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Section: Does “Mitochondrial Resuscitation” Help?mentioning

confidence: 99%

Microcirculation vs. Mitochondria—What to Target?

et al. 2020

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“…It was discovered to have additional metabolic functions, inhibiting mitochondrial membrane permeability and excessive ROS production. Cyclosporine was recently shown to exhibit these metabolic effects in pre-clinical rat [184] and porcine [185] [187,188] with no significant difference in adverse effects compared to controls [189]. However, improved neuroprotection or cognitive outcome in humans is yet to be confirmed.…”

Section: Cyclosporinementioning

confidence: 99%

Metabolism and inflammation: implications for traumatic brain injury therapeutics

Killen

Giorgi-Coll

Helmy

et al. 2019

Expert Review of Neurotherapeutics

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Introduction: Traumatic Brain Injury (TBI) is a leading cause of death and disability in young people, affecting 69 million people annually, worldwide. The initial trauma disrupts brain homeostasis resulting in metabolic dysfunction and an inflammatory cascade, which can then promote further neurodegenerative effects for months or years, as a 'secondary' injury. Effective targeting of the cerebral inflammatory system is challenging due to its complex, pleiotropic nature. Cell metabolism plays a key role in many diseases, and increased disturbance in the TBI metabolic state is associated with poorer patient outcomes. Investigating critical metabolic pathways, and their links to inflammation, can potentially identify supplements which alter the brain's long-term response to TBI and improve recovery. Areas covered: The authors provide an overview of literature on metabolism and inflammation following TBI, and from relevant pre-clinical and clinical studies, propose therapeutic strategies. Expert commentary: There is still no specific active drug treatment for TBI. Changes in metabolic and inflammatory states have been reported after TBI and appear linked. Understanding more about abnormal cerebral metabolism following TBI, and its relationship with cerebral inflammation, will provide essential information for designing therapies, with implications for neurocritical care and for alleviating long-term disability and neurodegeneration in post-TBI patients.

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“…The drug also has a short therapeutic window and needs continuous infusion over the first 3 days post injury to stabilize the mitochondria (109–112). Recent work with a new carrier in gyrencephalic animals is reportedly neuroprotective (113). A related drug, minocycline, although not tested in OBTT and initially used for a different purpose i.e., reducing neuroinflammation via ablation of activated microglia, was tested in human TBI and found to have no benefits (114) though the marker of inflammation was reduced.…”

Section: Can Insights Into Tbi Pathomechanism Explain Failure Of Pastmentioning

confidence: 99%

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI

Kassi

Mahavadi

Clavijo³

et al. 2019

Front. Neurol.

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Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including “The Lancet Neurology Commission” and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection.

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Neuroprotective Effects of Cyclosporine in a Porcine Pre-Clinical Trial of Focal Traumatic Brain Injury

Cited by 33 publications

References 85 publications

Microcirculation vs. Mitochondria—What to Target?

Microcirculation vs. Mitochondria—What to Target?

Metabolism and inflammation: implications for traumatic brain injury therapeutics

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI

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