Cardiopulmonary arrest (CA) remains one of the leading causes of death or disability in the USA. The chances of survival following CA are poor, despite fast medical emergency responses and better defibrillation techniques. The prevalent quandary in this field is the multi-factorial nature of CA: i.e. whole body ischemia, which compromises systemic blood parameters and cerebral, renal and cardiac functions, and consequent disruption of cerebral blood flow (CBF) and sympathetic over-stimulation, that results in severe and selective brain damage (i.e. neuronal cell death). Derangements of CBF occur hours after ischemia caused by acute hyperemia (increased CBF) and hypoperfusion (decreased CBF) and again one or several days after CA; there is hypoperfusion thought to be critical in CBF autoregulation detrimental to the brain.
Research Focus 1
Identifying novel factors that influence CBF autoregulation and innovative neuroprotective agents in the context of CA is our long-term research goal. We have uncovered a new vasotone regulatory agent, namely the release of palmitic acid methyl ester (PAME) (a vasodilator that is more potent than some nitric oxide donors and neuroprotective agent) and stearic acid methyl ester (SAME, a neuroprotective agent) from preganglionic neurons of the superior cervical ganglion (SCG) innervating major cerebral arteries throughout the brain. Identifying the physiological mechanism(s) of PAME/SAME may have high translational value for potentially providing new therapeutic treatment and prevention targets against the detrimental impacts of CA on the brain and expanding our knowledge of CBF autoregulation and neuroprotection by these fatty acid methyl esters. The consequences of CA may affect cerebral vascular tonicity by over-stimulation of sympathetic innervation on SCG-derived vessels resulting in CBF deficits in the extremely vulnerable CA1 region of the hippocampus under CA. We are also interested in understanding the physiological relevance and normal regulatory function in cerebral circulation of PAME/SAME beyond CA and explore its’ distribution in central and peripheral nervous systems.
Fatty acid methyl esters are inherently interesting and most of the functional aspects of fatty acid methyl esters still remain unknown. This is problematic due to the lack of specific biomarkers for fatty acids. Currently, it is not yet possible to detect the localization of a specific fatty acid due to the lack of specific radioactive or antibody labeling a specific fatty acid chain. Another major problem arises from the complexity and high variability of these fatty acids. Even if specific biomarkers do exist for PAME and SAME, the question of additional side chains and saturation (complete or incomplete saturated fatty acids) of a specific fatty acid remains problematic. Thus, currently we can only detect the presence of fatty acid methyl esters by utilizing mass spectrometry but the method cannot be used to directly determine fatty acid localization within tissue types. Our laboratory is currently developing biomarkers specific to PAME and SAME in order to better understand PAME/SAME physiology.
Research Focus 2
The second project in our laboratory is to investigate the sympathetic nervous system (SNS) as it relates to CA. The SNS innervates cerebral arteries to maintain vascular tone and autoregulation in the brain. One of the most prominent hallmarks of cerebral ischemia caused by CA is the inherent enhanced activity of the SNS after resuscitation. The consequences of CA (global cerebral ischemia) results in a rise in plasma catecholamine levels from the SNS. CA can induce excessive norepinephrine (NE) release, the major neurotransmitter released from the SNS, onto brain regions such as the hippocampus and cortex. The pathophysiological function of the SNS on CA-induced injury is rather controversial. Attenuation of the sympathetic signal to the brain has been reported to enhance ischemia-induced brain damage while, more favorable outcomes from ischemia-induced brain injury are associated with norepinephrine depletion. Therefore, our main goal is to delineate the pathophysiological mechanism(s) of the SNS after CA-induced brain injury.