Cyclosporin A Enhances Survival, Ameliorates Brain Damage, and Prevents Secondary Mitochondrial Dysfunction after a 30-Minute Period of Transient Cerebral Ischemia

Li, Ping An; Kristián, Tibor; He, Qing; Siesjö, Bo K.

doi:10.1006/exnr.2000.7459

Cited by 67 publications

(41 citation statements)

References 41 publications

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“…Another possibility would be the participation of mitochondria of inflammatory cells during longer periods of ischemia. The decline in the mitochondrial respiration after some hours of reperfusion in global ischemia of similar or longer-duration or focal ischemia with duration longer than 60 minutes has been observed by other authors 8,10,26 . These results were not observed in this study in which the reperfusion time was around 19 hours, suggesting that the effects of reperfusion were beneficial in this situation.…”

Section: Resultssupporting

confidence: 71%

“…Attempts have been made to establish time parameters to temporary ischemia without injuries to the brain using clinical and experimental studies [4][5][6] . Among several methods for evaluating the effects of the ischemic and reperfusion insults to the brain, the metabolic evaluation such as the mitochondrial respiration or measures of involved enzymatic activity, can give precocious information about the energetic state of the neuron and the functional capacity after reperfusion [6][7][8][9][10] . Ex-perimental studies showing the mitochondrial response to short period focal ischemia followed by reperfusion could not be found in the literature.…”

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confidence: 99%

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Functional evaluation of temporary focal cerebral ischemia: experimental model

Duarte

Campos²,

Colli³

2003

Arq. Neuro-Psiquiatr.

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-Objective: Despite cerebral ischemia being a frequent clinical pathologic state, the tolerance of neural tissue to oxygen absence and to reperfusion is controversial. This study aims to evaluate the effects of focal cerebral ischemia/reperfusion, by analyzing the mitochondrial respiration. Method: Sixty-four adult rats underwent focal cerebral ischemia by middle cerebral artery occlusion, during 15, 30 and 60 minutes, followed by 10 minutes or 19 hours of reperfusion. The effects of ischemia were analyzed measuring the O 2 consumption by mitochondria in the ischemic and non-ischemic areas. Results: There was compromise of the mitochondrial respiration after 30 and 60 minutes of ischemia, followed by 10 minutes of reperfusion but there was no alteration in this function after 19 hours of reperfusion. Conclusion: Compromise of the mitochondrial function occurred after 30 minutes of ischemia but, until one hour of ischemia, if the reperfusion was prolonged there was no evidence of ischemic/reperfusion injuries.KEY WORDS: focal brain ischemia, reperfusion, mitochondrial respiration.Avaliação funcional da isquemia cerebral focal temporária em modelo experimental Avaliação funcional da isquemia cerebral focal temporária em modelo experimental Avaliação funcional da isquemia cerebral focal temporária em modelo experimental Avaliação funcional da isquemia cerebral focal temporária em modelo experimental Avaliação funcional da isquemia cerebral focal temporária em modelo experimental RESUMO -Objetivo: Apesar da isquemia cerebral focal ser um estado patológico freqüente, a tolerância do tecido nervoso à ausência de oxigênio e à reperfusão é controversa. Este estudo visou avaliar os efeitos da isquemia/reperfusão cerebrais focais através da respiração mitocondrial. Método: Sessenta e quatro ratos adultos foram submetidos a isquemia cerebral focal por oclusão da artéria cerebral media durante 15, 30 e 60 minutos, seguida de reperfusão por 10 minutos e 19 horas. Os efeitos da isquemia/reperfusão foram analisados medindo-se o consumo de O 2 pelas mitocôndrias nas áreas isquêmicas e não isquêmicas. Resultados: A respiração mitocondrial mostrou-se alterada após 30 e 60 minutos de isquemia seguidos por 10 minutos de reperfusão mas apresentou-se inalterada após 19 horas de reperfusão. Conclusão: O comprometimento da função mitocondrial ocorreu após 30 minutos de isquemia, porém, até uma hora de isquemia e reperfusão prolongada não foram observadas alterações pós-isquemia/reperfusão. PALAVRAS-CHAVE: isquemia cerebral focal, reperfusão, respiração mitocondrial.

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Section: Resultssupporting

confidence: 71%

mentioning

confidence: 99%

Functional evaluation of temporary focal cerebral ischemia: experimental model

Duarte

Campos²,

Colli³

2003

Arq. Neuro-Psiquiatr.

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“…Numerous experimental studies and clinical observations have demonstrated that the immunosuppressant cyclosporin A (CsA), which inhibits mPT and promotes mitochondrial function, may be of therapeutic benefit in the treatment of acute traumatic brain injury (TBI), SCI, cerebral ischemia, and reperfusion injury following acute myocardial infarction [94][95][96][97][98][99][100][101][102][103]. Phase I clinical trials for the acute treatment of severe TBI have been performed, and follow-up trials have been proposed [104].…”

Section: Targeting the Mptp In Acute Scimentioning

confidence: 99%

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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Summary: Traumatic injury to the mammalian spinal cord is a highly dynamic process characterized by a complex pattern of pervasive and destructive biochemical and pathophysiological events that limit the potential for functional recovery. Currently, there are no effective therapies for the treatment of spinal cord injury (SCI) and this is due, in part, to the widespread impact of the secondary injury cascades, including edema, ischemia, excitotoxicity, inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signaling events. In addition, many of the signaling pathways associated with these cascades intersect and initiate other secondary injury events. Therefore, it can be argued that therapeutic strategies targeting a specific biochemical cascade may not provide the best approach for promoting functional recovery. A "systems approach" at the subcellular level may provide a better strategy for promoting cell survival and function and, as a consequence, improve functional outcomes following SCI. One such approach is to study the impact of SCI on the biology and function of mitochondria, which serve a major role in cellular bioenergetics, function, and survival. In this review, we will briefly describe the importance and unique properties of mitochondria in the spinal cord, and what is known about the response of mitochondria to SCI. We will also discuss a number of strategies with the potential to promote mitochondrial function following SCI.

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“…Such mitochondrial dysfunction plays a significant role in TBI-induced early neuropathological events, causing the loss of ATP and increased production of reactive oxygen species (Fiskum, 2000;Lifshitz et al, 2004;Sullivan et al, 2005;Wang, 2001). These effects, in turn, lead to cell death by either necrotic or apoptotic routes, since pro-apoptotic factors such as caspase C are also released from mitochondria (Kroemer and Reed, 2000;Lewen et al, 2001;Li et al, 1997;Li et al, 2000;Sullivan et al, 2002;Uchino et al, 2002;Zou et al, 1997). Similarly, caspase 3 activation has been linked to intra-axonal cytoskeletal damage that leads to axonal failure and disconnection (Bü ki et al, 2000;Ferrand-Drake et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…It has been proven effective in models of hypoglycemic brain damage (Ferrand-Drake et al, 2003;Friberg et al, 1998), while improving brain tissue oxygen consumption and cognitive performance after TBI (Alessandri et al, 2002). CsA's beneficial effects on infarct size and global ischemic damage have been demonstrated when the drug is given either pre-injury or post-ischemia (Friberg et al, 1998;Li et al, 2000;Yoshimoto and Siejo, 1999).…”

Section: Introductionmentioning

confidence: 99%

Safety and Tolerability of Cyclosporin A in Severe Traumatic Brain Injury Patients: Results from a Prospective Randomized Trial

Mazzeo

Brophy

Gilman

et al. 2009

Journal of Neurotrauma

100

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Cyclosporin A (CsA) has recently been proposed for use in the early phase after traumatic brain injury (TBI), for its ability to preserve mitochondrial integrity in experimental brain injury models, and thereby provide improved behavioral outcomes as well as significant histological protection. The aim of this prospective, randomized, double-blind, dual-center, placebo-controlled trial was to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of CsA in patients with severe TBI. Fifty adult severe TBI patients were enrolled over a 22-month period. Within 12 h of the injury patients received 5 mg=kg of CsA infused over 24 h, or placebo. Blood urea nitrogen (BUN), creatinine, hemoglobin, platelets, white blood cell count (WBC), and a hepatic panel were monitored on admission, and at 12, 24, 36, and 48 h, and on days 4 and 7. Potential adverse events (AEs) were also recorded. Neurological outcome was recorded at 3 and 6 months after injury. This study revealed only transient differences in BUN levels at 24 and 48 h and for WBC counts at 24 h between the CsA and placebo patients. These modest differences were not clinically significant in that they did not negatively impact on patient course. Both BUN and creatinine values, markers of renal function, remained within their normal limits over the entire monitoring period. There were no significant differences in other mean laboratory values, or in the incidence of AEs at any other measured time point. Also, no significant difference was demonstrated for neurological outcome. Based on these results, we report a good safety profile of CsA infusion when given at the chosen dose of 5 mg=kg, infused over 24 h, during the early phase after severe head injury in humans, with the aim of neuroprotection.

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Cyclosporin A Enhances Survival, Ameliorates Brain Damage, and Prevents Secondary Mitochondrial Dysfunction after a 30-Minute Period of Transient Cerebral Ischemia

Cited by 67 publications

References 41 publications

Functional evaluation of temporary focal cerebral ischemia: experimental model

Functional evaluation of temporary focal cerebral ischemia: experimental model

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

Safety and Tolerability of Cyclosporin A in Severe Traumatic Brain Injury Patients: Results from a Prospective Randomized Trial

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