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3. Vagus Nerve Stimulation in Ischemic Stroke

Author

Andalib, Sasan, Divani, Afshin A., Ayata, Cenk, Baig, Sheharyar, Arsava, Ethem Murat, Topcuoglu, Mehmet Akif, Cáceres, Eder Leonardo, Parikh, Vinay, Desai, Masoom J., Majid, Arshad, Girolami, Sara, and Di Napoli, Mario

Published
2023
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14. Migraine

Author

Ferrari, Michel D., Goadsby, Peter J., Burstein, Rami, Kurth, Tobias, Ayata, Cenk, Charles, Andrew, Ashina, Messoud, van den Maagdenberg, Arn M. J. M., and Dodick, David W.

Published
2022
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15. The novel ROCK2 selective inhibitor NRL-1049 preserves the blood-brain barrier after acute injury.

Author

Mulder, Inge A, Abbinanti, Matt, Woller, Sarah A, Ruschel, Joerg, Coutinho, Jonathan M, de Vries, Helga E, van Bavel, Ed, Rosen, Kenneth, McKerracher, Lisa, and Ayata, Cenk

Abstract

Endothelial blood-brain barrier (BBB) dysfunction is critical in the pathophysiology of brain injury. Rho-associated protein kinase (ROCK) activation disrupts BBB integrity in the injured brain. We aimed to test the efficacy of a novel ROCK2 inhibitor in preserving the BBB after acute brain injury. We characterized the molecular structure and pharmacodynamic and pharmacokinetic properties of a novel selective ROCK2 inhibitor, NRL-1049, and its first metabolite, 1-hydroxy-NRL-1049 (referred to as NRL-2017 hereon) and tested the efficacy of NRL-1049 on the BBB integrity in rodent models of acute brain injury. Our data show that NRL-1049 and NRL-2017 both inhibit ROCK activity and are 44-fold and 17-fold more selective towards ROCK2 than ROCK1, respectively. When tested in a mouse model of cortical cryoinjury, NRL-1049 significantly attenuated the increase in water content. Interestingly, 60% of the mice in the vehicle arm developed seizures within 2 hours after cryoinjury versus none in the NRL-1049 arm. In spontaneously hypertensive rats, NRL-1049 attenuated the dramatic surge in Evans Blue extravasation compared with the vehicle arm after transient middle cerebral artery occlusion. Hemorrhagic transformation was also reduced. We show that NRL-1049, a selective ROCK2 inhibitor, is a promising drug candidate to preserve the BBB after brain injury. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Which Spreading Depolarizations Are Deleterious To Brain Tissue?

Author

Shuttleworth, C. William, Andrew, R. David, Akbari, Yama, Ayata, Cenk, Balu, Ramani, Brennan, K. C., Boutelle, Martyn, Carlson, Andrew P., Dreier, Jens P., Fabricius, Martin, Farkas, Eszter, Foreman, Brandon, Helbok, Raimund, Henninger, Nils, Jewell, Sharon L., Jones, Stephen C., Kirov, Sergei A., Lindquist, Britta E., Maciel, Carolina B., Okonkwo, David, Reinhart, Katelyn M., Robertson, R. Meldrum, Rosenthal, Eric S., Watanabe, Tomas, and Hartings, Jed A.

Published
2020
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25. CADASIL mutations sensitize the brain to ischemia via spreading depolarizations and abnormal extracellular potassium homeostasis

Author

Oka, Fumiaki, Lee, Jeong Hyun, Yuzawa, Izumi, Li, Mei, von Bornstaedt, Daniel, Eikermann-Haerter, Katharina, Qin, Tao, Chung, David Y., Sadeghian, Homa, Seidel, Jessica L., Imai, Takahiko, Vuralli, Doga, Platt, Rosangela M., Nelson, Mark T., Joutel, Anne, Sakadzic, Sava, and Ayata, Cenk

Subjects
Gene mutations -- Research, Medical research, Medicine, Experimental, Cerebral ischemia -- Genetic aspects -- Risk factors -- Development and progression, Homeostasis -- Health aspects -- Genetic aspects, CADASIL -- Complications and side effects, Potassium imbalance -- Risk factors -- Genetic aspects -- Development and progression, Health care industry
Abstract

Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic form of small vessel disease characterized by migraine with aura, leukoaraiosis, strokes, and dementia. CADASIL mutations cause cerebrovascular dysfunction in both animal models and humans. Here, we showed that 2 different human CADASIL mutations (Notch3 R90C or R169C) worsen ischemic stroke outcomes in transgenic mice; this was explained by the higher blood flow threshold to maintain tissue viability compared with that in wild type (WT) mice. Both mutants developed larger infarcts and worse neurological deficits compared with WT mice, regardless of age or sex after filament middle cerebral artery occlusion. However, full-field laser speckle flowmetry during distal middle cerebral artery occlusion showed comparable perfusion deficits in mutants and their respective WT controls. Circle of Willis anatomy and pial collateralization also did not differ among the genotypes. In contrast, mutants had a higher cerebral blood flow threshold, below which infarction ensued, suggesting increased sensitivity of brain tissue to ischemia. Electrophysiological recordings revealed a 1.5- to 2-fold higher frequency of peri-infarct spreading depolarizations in CADASIL mutants. Higher extracellular [K.sup.+] elevations during spreading depolarizations in the mutants implicated a defect in extracellular [K.sup.+] clearance. Altogether, these data reveal a mechanism of enhanced vulnerability to ischemic injury linked to abnormal extracellular ion homeostasis and susceptibility to ischemic depolarizations in CADASIL., Introduction Cerebral autosomal dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most common monogenic small vessel disease, characterized by frequent migraine attacks with aura, progressive white matter degeneration, and [...]

Published
2022
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49. NAD + precursor nutritional supplements sensitize the brain to future ischemic events.

Author

Qu, Wensheng, Ralto, Kenneth M, Qin, Tao, Cheng, Yinhong, Zong, Weifeng, Luo, Xiang, Perez-Pinzon, Miguel, Parikh, Samir M, and Ayata, Cenk

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a redox cofactor critical for oxidative phosphorylation. Nicotinamide (NAM) and nicotinamide riboside (NR) are NAD+ precursors widely used as nutritional supplements to augment oxidative phosphorylation. Indeed, NAD+ precursors have been reported to improve outcomes in ischemic stroke when administered as a rescue therapy after stroke onset. However, we have also reported that enhanced reliance on oxidative phosphorylation before ischemia onset might worsen outcomes. To address the paradox, we examined how NAD+ precursors modulate the outcome of middle cerebral artery occlusion in mice, when administered either 20 minutes after reperfusion or daily for three days before ischemia onset. A single post-ischemic dose of NAM or NR indeed improved tissue and neurologic outcomes examined at 72 hours. In contrast, pre-ischemic treatment for three days enlarged the infarcts and worsened neurological deficits. As a possible explanation for the diametric outcomes, a single dose of NAM or NR augmented tissue AMPK, PGC1α, SIRT1, and ATP in both naïve and ischemic brains, while the multiple-dose paradigm failed to do so. Our data suggest that NAD+ precursor supplements may sensitize the brain to subsequent ischemic events, despite their neuroprotective effect when administered after ischemia onset. [ABSTRACT FROM AUTHOR]

Published
2023
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