Table 1.
In vivo efficacy studies of cyclosporine
| Model/species | Dose (mg/kg)/route/timing | Findings/conclusions |
|---|---|---|
| Impact acceleration—histology, biochemistry | ||
| IA/rats [46] | 10/IT/30 min before injury | CsA bolus before TBI preserved mitochondrial morphology and limited delayed axotomy and axonal damage |
| IA/rats [47] | 10/IT/30 min before injury | CsA bolus before TBI decreased neurofilament compaction and cytoskeletal damage |
| IA/rats [48] | 10/IT/30 min post-injury | CsA bolus after TBI decreased neurofilament compaction, calpain-induced axonal injury, and APP accumulation in damaged axons |
| IA + hypothermia/rats [49] | 10/IT (infusion)/40 min post-injury | Significant reduction in APP accumulation in CsA + rapid rewarming group |
| IA/rats [23] | 3, 10, 20, 30, 50/IV; 10/IT following injury (over 1 h by microsyringe infusion pump) | 10 mg/kg IV CsA gave a lower brain concentration of CsA vs. 10 mg/kg IT. 10 mg/kg IV CsA gave the greatest reduction in injured axon density vs. controls and was significantly more effective than 20 or 30 mg/kg IV |
| IA/rats [50] | 10/IT, 20/IV, 35/infusion 1 h 30 min post-injury | Significant neuroprotection with IT CsA (preservation of NAA and partial prevention of ATP loss). The 20 mg/kg IV dose failed to ameliorate biochemical damage; the 35 mg/kg dose showed 36% NAA recovery and 39% ATP restoration |
| Behavioral | ||
| LFPI/rats [51] | 10/IP/15 min post-injury + 28 daily boluses | Significant improvement in motor and sensorimotor functions. No beneficial effect on cognitive function |
| LFPI/rats [52] | 0.625, 18.75/IV/30 min post-injury for 5 h | Both CsA doses abolished the 25% decrease in O2 consumption (VO2) |
| 0.375, 18.75/IV/infusion 60 min preinjury + 2 h post-injury | 0.375 mg/kg CsA improved acute motor deficits. 0.375 and 18.75 mg/kg doses of CsA improved cognitive deficits.18.75 mg/kg worsened acute motor function | |
| FPI/rats [26] | 10, 20/IV/15 min and 24 h post-injury |
FPI: 10 mg/kg dose gave histological protection (20 mg/kg worsened working memory) CCI: 20 mg/kg dose impaired Morris water maze performance; neither dose showed benefit for any outcome PBBI: no benefit for any outcome; mortality increased with the 20 mg/kg dose, partly due to the solvent vehicle. No positive effects on biomarker levels in any of the models |
| CCI/rats [26] | ||
| PBBI/rats [26] | ||
| IA/sheep[53] | 10/IT/30 min post-injury | Reduction in APP mRNA 2 and 6 h post-injury |
| Electrophysiological | ||
| Midline FPI/rats [54] | 20/IP/15 min post-injury or 1 h post-injury | Administration at 15 min post-injury gave significant protection of the CAP area. Administration at 1 h did not significantly protect CAPs but was associated with atypical waveforms in N1 CAPs, including shorter CAPs and reduced refractoriness |
| Cortical contusion injury—histology, mitochondrial function, imaging | ||
| CCI/rats and mice [55] | 20, 40/IP/5 min before injury or 15 min post-injury + 24 h post-injury | All doses demonstrated a significant reduction in cortical damage in mice and rats. The lowest doses of CsA gave the greatest sparing of cortical tissue. No significant difference between pre- and post-treatment |
| 20, 40, 150/IP/5 min before injury (mice only) | ||
| CCI/rats [56] | 20/IP/15 min post-injury | Maintenance of mitochondrial transmembrane potential. Decrease in mPTP opening. Decrease in mitochondrial Ca2+. Decrease in ROS generation |
| CCI/rats [25] | 20/IP/15 min post-injury followed by 0 or 20/IP/24 h or 4.5, 10/SC pump for 7 days | Significant reduction in lesion volume for all groups. The best results with 10 mg/kg/day continuous infusion for 7 days resulting in 74% reduction in lesion volume |
| CCI/rats [57] | 20, 35/IV/1 h infusion 30 min post-injury | No significant change in brain water content and no exacerbation of brain edema with IV administration |
| CCI/rats [58] | 20/IP/boluses 15 min post-injury + 24 h post-injury | CsA significantly decreased the extent of damage and C-tau levels in the ipsilateral hippocampus |
| CCI/rats [59] | 20/IP/immediately post-injury | Significant decrease in Evans blue extravasation |
| CCI/mice [60] | 20/IP/15 min post-injury | Significantly decreased protein nitration and lipid peroxidation in mitochondria 12 h after injury; reversal of decrease in RCR, but not the decrease in ETS capacity and complex II activity in mitochondria |
| CCI/rats [61] | 20/IP + 10/SC per day through implanted pump for 72 h initiated 1, 3, 4, 5, 6, or 8 h post-injury | CsA treatment initiated at any of the post-injury times resulted in significantly less cortical damage. Treatment begun in the first 3 h was significantly more protective than that begun at 4 and 8 h |
| CCI/rats [62] | 20/IP/15 min post-injury | Improvement of respiration at 24 h by CsA in the more severely impaired synaptic population of isolated mitochondria |
| CCI/rats [6] | 20/IP/15 min post-injury + 10/SC infusion for 3 days | Significant reduction of 4-HNE binding to mitochondrial proteins at 72h by CsA, but no effect on α-spectrin degradation or respiration of isolated mitochondria |
| CCI/mice [63] | 20/IP/15 min post-injury + 10/IP every 24 h for 5 days | Improvement of BBB stabilization and closure by CsA |
| CCI/rats [64] | 20/IP immediately post-injury | Decrease of brain edema, lipid peroxidation, and ultrastructural neurodestruction by CsA |
| CCI/piglets [29, 30] | 20/IV infusion for 5 days | CsA reduced the cortical and subcortical lesion volume by 35% and improved fractional anisotropy scores and MRS metabolite levels |
| Behavioral + histology | ||
| CCI/rats [65] | 20/IP/3 boluses 1 h post-injury + 24 h post-injury + 3 days post-injury | CsA had no significant effects on behavioral tests in rats |
| CCI/mice [66] | 20/IP/15 min post-injury | Significant decrease in CSF levels of alpha-II-SBDPs |
| 20/IP/15 min post-injury + 24 h post-injury | Significantly improved motor function 48 h and 7 days post-injury. Significant decrease in the damaged area in the ipsilateral hemisphere 7 days post-injury | |
| CCI/Mice [67] | 20/IP/day or 1.26/IV/days for 7–14 days (lipoprotein biomimetic nanocarrier containing CsA) | Significantly reduced neuronal damage, astrogliosis, and microglial activation and improved Morris water maze performance |
| CCI/CypD-knockout mice [5] | 20/IP/15 min post-injury + 24 h post-injury | CypD knockout improved mitochondrial bioenergetics, tissue sparing, and CA3 neuronal loss but not Morris water maze performance. CsA provided further tissue sparing in CypD-knockout mice |
| Electrophysiological | ||
| CCI/rats [68] | 20/IP/15 min post-injury | CsA prevented LTP impairment and LTD in CA1-CA3 |
| Aseptic cerebral injury | ||
| Aseptic cerebral injury/mice [69] | 50/IP/2 h preinjury + 2 h post-injury | Decreases in density of apoptotic cells and size of injury (MRI). No significant change in neutrophil infiltration |
| Combination studies and other models | ||
| CCI/rats [24] | 1, 5, 10, 20, 40/IP boluses 15 min + 24 h post injury and 20/IP 15 min, 1 h, 6 h, or 24 h post injury + 20/IP after an additional 24 h |
CCI: significant reduction in lesion volume for all groups. The best results with 20 mg/kg, which also showed effects at 6 and 24 h post-injury. Reduction of BBB disruption FPI: significant effect of both CsA groups combined compared to placebo |
| FPI/mice [24] | 20, 40/IP boluses 15 min + 24 h post injury | |
| Rotating dental drill/rats (immature) [70] | 20/IP/20 min post-injury + 24 h post-injury | CsA treatment significantly decreased brain weights, but similar effect from vehicle alone |
| CCI/rats (immature) [71] | 20/IP/15 min post-injury |
Both models: preserved mitochondrial bioenergetics and decreased hemispheric RCR differences Piglets: lactate:pyruvate ratio maintained, cerebral blood flow significantly increased, injured brain volume reduced by 42% |
| RNR/piglets [71] | 2 × 20/IV/5 min post-injury + 12 h post-injury | |
| CCI/piglets [72] | 10, 20, 40, 60 per day/IV/1 h, 6 h post-injury |
CCI: 60 mg/kg at 1 h effective: ≥50% positive outcome rate (neuropathology plus mitochondrial function). 10, 20, and 60 mg/kg at 6 h effective: ≥45% positive outcome rate RNR: no CsA doses effective in the 1 h group. The 20 mg/kg dose in the 6 h group met effectiveness criteria (≥50% positive outcome rate) |
| RNR/piglets [72] | 10, 20, 40, 60 per day/IV/1 h, 6 h post-injury | |
4-HNE 4-hydroxynonenal, APP amyloid precursor protein, ATP adenosine triphosphate, BBB blood-brain barrier, CAP compound action potential, CBF cerebral blood flow, CCI controlled cortical impact, CsA cyclosporine, CSF cerebrospinal fluid, CypD cyclophilin D, ELISA enzyme-linked immunosorbent assay, ETS electron transport system, FPI fluid percussion injury, IA impact acceleration, IP intraperitoneal, IT intrathecal, IV intravenous, LFPI lateral fluid percussion injury, LTD long-term depression, LTP long-term potentiation, mPTP mitochondrial permeability transition pore, MRI magnetic resonance imaging, MRS magnetic resonance spectroscopy, MWM Morris water maze, NAA N-acetylaspartate, PBBI penetrating ballistic-like brain injury, RCR respiratory control ratio, RNR rapid nonimpact rotational, ROS reactive oxygen species, SBDPs spectrin breakdown products, SC subcutaneous, TBI traumatic brain injury