Comparative Neuroprotective Effects of Cyclosporin a and NIM811, a Nonimmunosuppressive Cyclosporin a Analog, following Traumatic Brain Injury

Abstract

Earlier experiments have shown that cyclosporin A (CsA) and its non-calcineurin inhibitory analog NIM811 attenuate mitochondrial dysfunction after experimental traumatic brain injury (TBI). Presently, we compared the neuroprotective effects of previously determined mitochondrial protective doses of CsA (20 mg/kg intraperitoneally) and NIM811 (10 mg/kg intraperitoneally) when administered at 15 mins postinjury in preventing cytoskeletal (a-spectrin) degradation, neurodegeneration, and neurological dysfunction after severe (1.0 mm) controlled cortical impact (CCI) TBI in mice. In a first set of experiments, we analyzed calpain-mediated a-spectrin proteolysis at 24 h postinjury. Both NIM811 and CsA significantly attenuated the increased a-spectrin breakdown products observed in vehicle-treated animals (P < 0.005). In a second set of experiments, treatment of animals with either NIM811 or CsA at 15 mins and again at 24 h postinjury attenuated motor function impairment at 48 h and 7 days (P < 0.005) and neurodegeneration at 7 days postinjury (P < 0.0001). Delayed administration of NIM811 out to 12 h was still able to significantly reduce a-spectrin degradation. These results show that the neuroprotective mechanism of CsA involves maintenance of mitochondrial integrity and that calcineurin inhibition plays little or no role because the non-calcineurin inhibitory analog, NIM811, is as effective as CsA.

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

“…In a recent study using an animal model of TBI, NIM811 treatment increased cortical tissue sparing, improved mitochondrial function, and reduced oxidative damage in adult rats [128]. In a follow-up study, the cytoprotective effects of NIM811 were similar to CsA, providing strong evidence that the actions of both compounds function to maintain mitochondrial integrity [129]. Interestingly, in this same study, delaying NIM811 administration by 12 h following injury was effective in preventing cytoskeletal degradation.…”

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

“…A transparent platform (10 cm in diameter) was submerged 0.5 cm below the surface of the opaque water. Starting on post-injury day (PID) 14, the mice were trained to find the hidden submerged platform located in the northeast (NE) quadrant of tank for 4 consecutive days (PID [14][15][16][17]. The mice underwent four trials per day, starting from a randomly-selected release point (east, south, west, and north).…”

“…[6][7][8][9] CCI can cause intracerebral hemorrhage, cytotoxic and vasogenic brain edema, neuronal loss, and motor and cognitive deficits. [10][11][12][13][14][15][16] Both behavioral and histological outcomes are injury-severity dependent, as demonstrated by varying impact depth and/or velocity in rats, 17,18 or mice. 11,12,19 In the present study we compared multiple behavioral outcomes as a function of injury severity in the mouse CCI model to assess which tests or test combinations best reflect changes of lesion volume and cell loss in specific anatomical regions.…”

Multifunctional Drugs for Head Injury

“…175,176 Although CyA also inhibits calcineurin, 169 it is thought that the effects on mitochondrial activity are pivotal to its neuroprotective action. 177,178 Indeed, compared with FK506, a related immunosuppressant that inhibits calcineurin as effectively as CyA does, 169,179 CyA was superior in protecting against ischemic damage [177][178][179][180] and hypoglycemic brain injury, 181 presumably because of the superior ability of CyA to inhibit the mitochondrial permeability transition. 180 In addition to the suggestion that CyA completely inhibits excitotoxin-induced neuronal cell death, 182 there is also a dose-dependent inhibition of amyloid precursor protein accumulation 183 and of traumatic axonal injury after TBI, 184 which may account for the reduced number of disconnected and dysfunctional axons following impact acceleration TBI.…”