Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111)

Bon H. Verweij, Jan Paul Muizelaar, Federico C. Vinas, Parti L. Peterson, Ye Xiong, C. P. Lee

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain linked oxidative phosphorylation was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX- 111 at 4 mg kg-1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-111 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAD-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (RCI) and ATP synthesis (P/O ratio), and the energy linked Ca2+ transport. In order to assess the applicability of these data to the clinical setting, we have initiated studies with brain tissue which has to be resected during surgical treatment. Five patients suffered from brain trauma, one from intracranial hypertension due to stroke (noninfarcted tissue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension and the patient with epilepsy were tightly coupled with good respiratory rates with glutamate and malate as substrates, and high P/O ratios. The rates of respiration and ATP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These results indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metabolism. The time window for the effect of 5NX-111 in mitochondrial function and the (preliminary) similarity between mitochondrial dysfunction in experimental animals and humans make the drug appear to be well suited for clinical trials in severe head injury.

Original languageEnglish (US)
Pages (from-to)334-339
Number of pages6
JournalNeurological Research
Volume19
Issue number3
StatePublished - 1997
Externally publishedYes

Fingerprint

N-Type Calcium Channels
Calcium Channel Blockers
Brain Injuries
Brain
Intracranial Hypertension
Respiratory Rate
Electron Transport
Calcium
Epilepsy
Mitochondria
Wounds and Injuries
Adenosine Triphosphate
Stroke
Oxidative Phosphorylation
Mitochondrial Membranes
Succinic Acid
Craniocerebral Trauma
Intravenous Administration
NAD
Energy Metabolism

Keywords

  • Brain mitochondria
  • Ca channel blocker
  • Ca
  • Traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). / Verweij, Bon H.; Muizelaar, Jan Paul; Vinas, Federico C.; Peterson, Parti L.; Xiong, Ye; Lee, C. P.

In: Neurological Research, Vol. 19, No. 3, 1997, p. 334-339.

Research output: Contribution to journalArticle

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