Age-related decrease in cerebrovascular-derived neuroprotective proteins: Effect of acetaminophen

Abstract

As the population ages, the need for effective methods to maintain brain function in older adults is increasingly pressing. Vascular disease and neurodegenerative disorders commonly co-occur in older persons. Cerebrovascular products contribute to the neuronal milieu and have important consequences for neuronal viability. In this regard vascular derived neuroprotective proteins, such as vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), and pituitary adenylate cyclase activating peptide (PACAP) are important for maintaining neuronal viability, especially in the face of injury and disease. The objective of this study is to measure and compare levels of VEGF, PEDF and PACAP released from isolated brain microvessels of Fischer 344 rats at 6, 12, 18, and 24 months of age. Addition of acetaminophen to isolated brain microvessels is employed to determine whether this drug affects vascular expression of these neuroprotective proteins. Experiments on cultured brain endothelial cells are performed to explore the mechanisms/mediators that regulate the effect of acetaminophen on endothelial cells. The data indicate cerebrovascular expression of VEGF, PEDF and PACAP significantly decreases with age. The age-associated decrease in VEGF and PEDF is ameliorated by addition of acetaminophen to isolated brain microvessels. Also, release of VEGF, PEDF, and PACAP from cultured brain endothelial cells decreases with exposure to the oxidant stressor menadione. Acetaminophen treatment upregulates VEGF, PEDF and PACAP in brain endothelial cells exposed to oxidative stress. The effect of acetaminophen on cultured endothelial cells is in part inhibited by the selective thrombin inhibitor hirudin. The results of this study suggest that acetaminophen may be a useful agent for preserving cerebrovascular function. If a low dose of acetaminophen can counteract the decrease in vascular-derived neurotrophic factors evoked by age and oxidative stress, this drug might be useful for improving brain function in the elderly.

Aging-Induced Modulation of Pituitary Adenylate Cyclase-Activating Peptide- and Vasoactive Intestinal Peptide-Induced Vasomotor Responses in the Arteries of Mice

“…The vascular relaxation to PACAP1-38 is reduced with aging, which is similar to our previous observations in old rats [11]. An age-related decrease in PACAP mRNA and protein levels [16,31] can alter PACAP-induced relaxation. Accordingly, in the old rat brain, Lee et al [26] reported increased PAC1R and unchanged VPAC2R levels with aging, which implies the adaptation of the PACAP system for either compensation (in the form of receptor overexpression) or switch to “alternative” PACAP-mediated responses (most likely VIP).…”

“…Therefore, VIP may stimulate the same second level signaling related to PACAP, thus it can counterbalance the increased contractility. These findings could have physiological importance as VIP can provide a counterbalancing mechanism preserving vasodilation in PACAP-deficiency or PACAP-insufficiency, which can be present in pathological conditions [14] and aging [16]. …”

“…In contrast, these levels decrease with aging. Tripathy et al [16] reported that the cerebrovascular level of PACAP is higher in young rats and lower in old rats. An interesting observation has been made regarding PACAP and VIP receptors in the brain of old rats showing increased PAC1R, decreased VPAC1R, and unchanged VPAC2R levels [26,27].…”

“…In our recent study on rats, we have observed that relaxations induced by PACAP1-38 were reduced in the arteries of older rats [11]. Studies have also shown an age-related reduction of PACAP levels in cerebral microvessels [16,17]. In addition, Banki et al [17] reported that reduced levels of PACAP lead to impaired angiogenic capacity of the cerebral microvasculature in older age.…”

PACAP Enhances Barrier Properties of Cerebral Microvessels

“…We also showed that microvascular cerebral endothelial cells expressed PACAP. In accordance, isolated brain microvessels have been shown to release PACAP, e.Proofing http://eproofing.springer.com/printpage.php?token=GAdkHsZ-KwYI... which is decreasing with age (Tripathy et al 2012 ).…”