A Review of Laboratory and Clinical Data Supporting the Safety and Efficacy of Cyclosporin A in Traumatic Brain Injury

Abstract

For decades, cyclosporin A (CsA) has proved to be safe and effective for use in transplantation. In the past 10 years, this agent has shown neuroprotective effects in animal models of traumatic brain injury (TBI). This review article provides a critical overview of the literature on CsA neuroprotective effects in animal studies and current findings of clinical trials in the treatment of TBI with an emphasis on the possible CsA molecular mechanism of action. Animal data provide compelling evidence of the therapeutic benefits of CsA in TBI, but the outcome indices are heterogeneous with respect to the animal model of TBI as well as the route, dose, and timing of CsA administration. Similarly, clinical studies (phase II trials) adapting almost identical patient inclusion criteria have demonstrated the safety of CsA use in TBI, but the clinical trials are also heterogeneous based on study design, especially with regard to the variable timing of CsA administration after TBI. In view of the translational shortcomings of the preclinical studies and the rather pilot nature of the limited clinical trials that recently reached phase III, we offer guidance on the future directions of laboratory investigations on CsA that could improve the safety and efficacy of this agent in subsequent larger clinical trials.

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms

“…Immunosuppressants exert therapeutic benefits by themselves as standalone therapy (i.e. cyclosporine A), even without stem cells, as shown by us and other groups (Tajiri et al, 2016; Osman et al, 2011; Lulic et al, 2011; Ishii et al, 2013; Furuichi et al, 2003). However, most of these therapeutic effects have been observed when immunosuppressants are delivered prior to or immediately after the brain insults in pre-clinical models of CNS disorders.…”

Brain Region‐Specific Histopathological Effects of Varying Trajectories of Controlled Cortical Impact Injury Model of Traumatic Brain Injury

“…Blast injury, which is a clinically relevant TBI model [12][13][14][15], is technically challenging to recreate in animal models; thus, most TBI approaches focus on a specific type of injury, that is, targeting the cortex [8,[16][17][18][19][20]. The present study offers an alternative model in capturing the clinical scenario of varying injuries in TBI.…”

Medical Management of the Severe Traumatic Brain Injury Patient

“…Several studies have shown that cyclosporine-A is safe and tolerable in humans, with at least no negative impact on outcomes or mortality [90–91]. Lulic et al have reviewed the shortcomings of the cyclosporine-A preclinical and clinical trials, especially with regard to the heterogeneity of timing of administration of the drug, and have offered guidance for future studies, to clarify the role of cyclosporine in sTBI [104]. …”

“…From the standpoint of prognostication, CT grading systems such as the Marshall CT classification [127] and Rotterdam CT score [9] have been incorporated into the IMPACT and CRASH prediction models [104–105]. Yet despite the widespread use of head CT in the diagnostic and prognostic evaluation of patients with sTBI, multiple studies have shown that MRI provides higher sensitivity for detecting prognostically relevant intracerebral lesions, particularly traumatic axonal injury[128–131].…”