In gratitude of the loyal support of our members, the CNS is offering complimentary 2021 Annual Meeting registration to all members! Learn more.

  • Successful treatment of mitochondrial dysfunction after vasospasm in translational animal model

    Final Number:
    4067

    Authors:
    Axel Forsse MD; Frantz Rom Poulsen MD, PhD; Troels Nielsen MD, PhD; Jan B Gramsbergen PhD; Carl-Henrik Nordstrom MD, PhD; Kevin Nygaard BS

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2017 Annual Meeting - Late Breaking Science

    Introduction: A wide range of acute cerebral pathologies lead to mitochondrial dysfunction. Amongst these subarachnoid haemorrhage, where metabolic alterations in the vasospasm phase is especially detrimental(1,2). Earlier studies have described a specific pattern and method of diagnosis for this metabolic through microdialysis(3,4). There are currently no documented treatments for mitochondrial dysfunction in clinical use, but several compounds have shown great potential(7).

    Methods: We have modified a rat model with endothelin-1 induced cerebral vasospasm to create a translational setting in which to test effects of pharmacological intervention on post-ischemic mitochondrial dysfunction. The dialysate was analysed using an ISCUS flex analyser (MDialysis®, Stockholm). LP-ratio was calculated for each time-point and results were analysed statistically using a mixed effect model (STATA 14.2). Rat brains were cryopreserved, sectioned and stained. Infarct sizes were quantified using the Cavalieri-principle.

    Results: Rats were randomly assigned to treatment (Cyclosporin A-emulsion) or vehicle, administered immediately after induction of transient ischemia. Cerebral microdialysate was analysed in 15 min intervals. LP-ratios in the CsA treatment group were significantly lower after reperfusion (mean 66.6% point, P=0.006) showing near-normalization of cerebral metabolism compared to the vehicle controls. Infarction sizes were smaller in the treatment group with a mean difference of 34% (Mann-Whitney Test Striatum P=0.02).

    Conclusions: Cerebral post-ischemic dysfunctional metabolism is amenable to medical treatment. High dosage CsA (15mg/kg i.v.) ameliorates post-ischemic LP-ratio, a marker of cerebral mitochondrial function, in the acute phase. The metabolic results are corroborated by the infarction size estimations, with a considerable difference in favour of the treatment group.

    Patient Care: Potentially through the introduction of new pharmacological treatments for patients suffering of subarachnoid hemorrhage and other neurocritical conditions involving mitochondrial dysfunction.

    Learning Objectives: After this oral presentation, participants will have learned neurosurgically relevant cellular physiology (mitochondrial metabolism) in cerebrovascular disease, important aspects in designing translational animal models and insights in the effects of acute phase medical treatment of cerebral vasospasm.

    References: References 1Poulsen FR, Schulz M, Jacobsen A, Andersen ÅB, Larsen L, Schalén W, Nielsen TH, Nordström CH. Bedside evaluation of cerebral energy metabolism in severe community acquired bacterial meningitis. Neurocrit Care. 2015 Apr;22(2):2218. 2Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993; 34(2): 21622. 3Nielsen TH, Bindslev TT, Pedersen SM, Toft P, Olsen NV, Nordström CH. Cerebral energy metabolism during induced mitochondrial dysfunction. Acta AnaesthesiolScand 2013;57:229–35. 4Nielsen TH, Olsen NV, Toft P, Nordström CH. Cerebral energy metabolism during mitochondrial dysfunction induced by cyanide in piglets. Acta Anaesthesiol Scand 2013;57:793–801.5Yonutas HM, Vekaria HJ, Sullivan PG Mitochondrial specific therapeutic targets following brain injury. Brain res. 2016;1640:77-93.

We use cookies to improve the performance of our site, to analyze the traffic to our site, and to personalize your experience of the site. You can control cookies through your browser settings. Please find more information on the cookies used on our site. Privacy Policy