Anesthesia Neurotoxicity in Congenital Heart Disease
Abstract
Significant neurological impairment is emerging as one of the most important challenges for survivors of complex neonatal cardiac surgery. Recent clinical studies have shown that prolonged anesthesia for neonatal cardiac surgery early in life can damage the developing brain. Cardiopulmonary bypass (CPB) that is an assist system for cardiac surgery causes systemic inflammation during surgery. In addition, both deep hypothermic circulatory arrest (DHCA) and low flow cerebral perfusion -- techniques necessary for complex cardiac repair -- cause relative or complete cerebral ischemia under hypothermia and expose neonatal brains to reperfusion and reoxygenation injury. Prolonged anesthesia and CPB are indispensable for the care of children with complex congenital heart disease (CHD); however, the cellular and molecular mechanisms whereby anesthesia and cardiac surgery impact cortical development are poorly understood, thereby inhibiting development of effective treatment to minimize surgery-induced neurotoxicity. Various operative factors such as anesthetic agents and inflammation activate caspases in the developing brain. Although caspase activation has been used widely as the standard measure for cell death, it does not always lead to cell death but rather alters cellular status. Indeed, there has been little evidence for a reduction of cell numbers associated with neonatal anesthesia neurotoxicity. Consistently, our mouse studies have shown no reduction of cortical neurons after activation of caspases. We have also observed increases of fragmented actin and cleaved tubulin -- markers for caspase-mediated non-apoptotic degeneration in neuros -- in anesthesia-exposed cortices indicating the primary effects of caspase activation on non-apoptotic processes. The most common neurologic deficit seen in children after CHD repair is impairment of fine and gross motor skill development. Our data show that non-apoptotic caspase activation in the neonatal mouse brain impairs fine and gross motor skill learning. Consistent with these findings, we have found that extensive caspase activation after CPB did not change the number of neurons but did alter cortical microstructures. These results have led to our primary hypothesis that extensive caspase activation due to the global impact of cardiac surgery leads to non-apoptotic neuronal degeneration thereby contributing to neurological deficits in CHD. Given that caspase is an important enzyme during development, long-term caspase inhibition potentially has undesirable side effects. Our proposed studies therefore will test a potent pan-caspase inhibitor, Q-VD-OPh, in a limited timeframe that specifically targets caspase activation. Notably, inhibition of caspase in this crucial period improves impairments of fine and gross motor skill learning in mice. To test our central hypothesis and design new neuroprotective treatment in children with CHD, the proposed studies will use a cross-species approach in our unique piglet model of CPB (Aims 1 and 2) as well as a well-established mouse model of neonatal anesthesia (Aim 3). Aim 1: Determine the effects of surgery on caspase-induced non-apoptotic neuronal degeneration by prolonged anesthesia. Obvious difficulties prohibit distinguishing anesthesia neurotoxicity from the overall impact of surgery in children with CHD. We hypothesize that systemic inflammation and reoxygenation resulting from CPB/DHCA exacerbate caspase-induced non-apoptotic neuronal degeneration due to prolonged anesthesia. In the piglet model, we will first determine whether CPB exacerbates the effects of anesthesia at the cellular, microstructural, and molecular levels. Aim 2: Determine the effects of brief caspase inhibition on neuronal degeneration and cortical dysmaturation after cardiac surgery. We will test the hypothesis that brief inhibition of caspase activation is a potential treatment to limit the adverse impact of neonatal cardiac surgery. Th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010199
Entities
People
- Nobuyuki Ishibashi
Organizations
- United States Army