Hypertension Exacerbates Cerebrovascular Oxidative Stress Induced by Mild Traumatic Brain Injury: Protective Effects of the Mitochondria-Targeted Antioxidative Peptide SS-31.

Abstract

Traumatic brain injury (TBI) induces cerebrovascular oxidative stress, which is associated with neurovascular uncoupling, autoregulatory dysfunction, and persisting cognitive decline in both pre-clinical models and patients. However, single mild TBI (mTBI), the most frequent form of brain trauma, increases cerebral generation of reactive oxygen species (ROS) only transiently. We hypothesized that comorbid conditions might exacerbate long-term ROS generation in cerebral arteries after mTBI. Because hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive and spontaneously hypertensive rats (SHR) and assessed changes in cytoplasmic and mitochondrial superoxide (O2-) production by confocal microscopy in isolated middle cerebral arteries (MCA) 2 weeks after mTBI using dihydroethidine (DHE) and the mitochondria-targeted redox-sensitive fluorescent indicator dye MitoSox. We found that mTBI induced a significant increase in long-term cytoplasmic and mitochondrial O2- production in MCAs of SHRs and increased expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit Nox4, which were reversed to the normal level by treating the animals with the cell-permeable, mitochondria-targeted antioxidant peptide SS-31 (5.7 mg kg-1 day-1, i.p.). Persistent mTBI-induced oxidative stress in MCAs of SHRs was significantly decreased by inhibiting vascular NADPH oxidase (apocyinin). We propose that hypertension- and mTBI-induced cerebrovascular oxidative stress likely lead to persistent dysregulation of cerebral blood flow (CBF) and cognitive dysfunction, which might be reversed by SS-31 treatment.

• Authors: Andras Czigler, Luca Toth, Nikolett Szarka, Gergely Berta, Kriszitina Amrein, Endre Czeiter, Dominika Lendvai-Emmert, Kornelia Bodo, Stefano Tarantini, Akos Koller, Zoltan Ungvari, Andras Buki, Peter Toth
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 36 Issue 23 Pg. 3309-3315 (12 01 2019) ISSN: 1557-9042 [Electronic] United States
• PMID: 31266393 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Neuroprotective Agents
• Oligopeptides
• arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide

Topics

• Animals
• Antioxidants (administration & dosage)
• Brain Concussion (complications, drug therapy, metabolism)
• Drug Delivery Systems (methods)
• Hypertension (complications, drug therapy, metabolism)
• Male
• Mitochondria (drug effects, metabolism)
• Neuroprotective Agents (administration & dosage)
• Oligopeptides (administration & dosage)
• Oxidative Stress (drug effects, physiology)
• Rats
• Rats, Inbred SHR
• Rats, Wistar