title: 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.
authors.affiliation: Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
authors.forename: Debjani
authors.initials: D
authors.lastname: Tripathy
authors.forename: Alma
authors.initials: A
authors.lastname: Sanchez
authors.forename: Xiangling
authors.initials: X
authors.lastname: Yin
authors.forename: Joseph
authors.initials: J
authors.lastname: Martinez
authors.forename: Paula
authors.initials: P
authors.lastname: Grammas
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000375:Aging; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005136:Eye Proteins / Q000096:biosynthesis; D008833:Microcirculation / Q000187:drug effects; D009414:Nerve Growth Factors / Q000096:biosynthesis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D015843:Serpins / Q000096:biosynthesis; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D005136:Eye Proteins; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015843:Serpins; D013917:Thrombin; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor