Therapeutic Window Analysis of the Neuroprotective Effects of Cyclosporine A after Traumatic Brain Injury

Abstract

Mitochondrial dysfunction plays a pivotal role in secondary cell death mechanisms following traumatic brain injury (TBI). Several reports have demonstrated that inhibition of the mitochondrial permeability transition pore with the immunosuppressant drug cyclosporine A (CsA) is efficacious. Accordingly, CsA is being moved forward into late-stage clinical trials for the treatment of moderate and severe TBI. However, several unknowns exist concerning the optimal therapeutic window for administering CsA at the proposed dosages to be used in human studies. The present study utilized a moderate (1.75 mm) unilateral controlled cortical impact model of TBI to determine the most efficacious therapeutic window for initiating CsA therapy. Rats were administered an IP dose of CsA (20 mg/kg) or vehicle at 1, 3, 4, 5, 6, and 8 h post-injury. Immediately following the initial IP dose, osmotic mini-pumps were implanted at these time points to deliver 10 mg/kg/d of CsA or vehicle. Seventy-two hours following the initiation of treatment the pumps were removed to stop CsA administration. Quantitative analysis of cortical tissue sparing 7 days post-injury revealed that CsA treatment initiated at any of the post-injury initiation times out to 8 h resulted in significantly less cortical damage compared to animals receiving vehicle treatment. However, earlier treatment begun in the first 3 h was significantly more protective than that begun at 4 and 8 h. Treatment initiated at 1 h post-injury (∼68% decrease) was not significantly different than that seen at 3 h (∼46% decrease), but resulted in significantly greater cortical tissue sparing compared to CsA treatment initiated at least 4 h post-injury (28% decrease). Together these results illustrate the importance of initiating therapeutic interventions such as CsA as soon as possible following TBI, preferably within 4 h post-injury, to achieve the best possible neuroprotective effect. However, the drug appears to retain some protective efficacy even when initiated as late as 8 h post-injury.

Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

“…Based on our observations and evidence from experimental models, we propose that the mitochondrial structural alterations that occur in human cortical TBI tissue are associated with both perturbations in mitochondrial dynamics and with osmotic swelling associated with mitochondrial permeability transition (MPT) pore openings. 2,[57][58][59][60] It has now been demonstrated that inhibition of the MPT after TBI is a viable neuroprotective approach [61][62][63] and can improve the favorable outcomes of severe TBI patients. 64,65 The several interrelated mitochondrial dynamic processes, such as fusion, fission, anterograde and retrograde transport in axons, turnover, and interaction with cytoskeleton and other organelles, form a complex interacting network that governs mitochondrial function and thereby cellular integrity.…”

Serum Glial Fibrillary Acidic Protein Predicts Tissue Glial Fibrillary Acidic Protein Break-Down Products and Therapeutic Efficacy after Penetrating Ballistic-Like Brain Injury

“…Surprisingly the lower dose (2.5 mg/kg) was more effective than the higher dose (5 mg/kg). CsA has been shown to have an early therapeutic window and to inhibit a myriad of molecular processes and histological outcomes including reduced brain tissue BDP generation and decreased lesion volume [50][51][52] . To our knowledge, this is the first study to indicate that acute serum GFAP correlated to BDPs as well as neurobehavioral metrics.…”

Combination therapy with melatonin and dexamethasone in a mouse model of traumatic brain injury

“…The half-lives of melatonin and DEX are 27 and 200 min respectively (Cevc & Blume 2004, Venegas et al 2012. Several recent results have illustrated the importance of initiating therapeutic interventions as soon as possible following TBI, preferably within 4 h post-injury, to achieve the best possible neuroprotective effect (Sullivan et al 2011). …”