Thalidomide inhibition of vascular remodeling and inflammatory reactivity in the quinolinic acid-injected rat striatum.
Effects of thalidomide administration on vascular remodeling, gliosis and neuronal viability have been studied in excitotoxin-injected rat striatum. Intrastriatal injection of quinolinic acid (QUIN) caused time-dependent changes (durations of 6 h, 1 and 7 d post-injection) in vascular remodeling. QUIN excitotoxic insult was associated with increased numbers of vessels (laminin or collagen IV markers) demonstrating considerable abnormalities in morphology, including short fragments and vascular loops. Non-lesioned striatum, with injection of phosphate buffer solution (PBS) as a vehicle, showed no evidence for vascular remodeling. A maximal extent of vascular remodeling was measured at 1 d post-QUIN and was correlated with marked increases in microgliosis (ED1 marker) and astrogliosis (glial fibrillary acidic protein [GFAP] marker) relative to control PBS injection. Double staining of laminin with ED1 and GFAP demonstrated areas of close association of glial cells with blood vessels. Treatment of QUIN-injected animals with the anti-inflammatory compound, thalidomide significantly inhibited vascular remodeling (by 43%) and reduced microgliosis (by 33%) but was ineffective in modifying extents of astrogliosis. Intrastriatal QUIN injection was associated with a marked loss of striatal neurons relative to non-lesioned control with thalidomide treatment exhibiting a significant degree of neuroprotection (24% recovery) against QUIN-induced neurotoxicity. These results suggest close links between microglial-mediated inflammatory responses and vascular remodeling, with inflammatory reactivity associated with, and contributing to, neuronal damage in excitotoxically-lesioned striatum.
Ryu
J K
JK
Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, 2176 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada.
Jantaratnotai
N
N
McLarnon
J G
JG
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D005911:Gliosis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013792:Thalidomide / Q000494:pharmacology*; D013997:Time Factors
D020533:Angiogenesis Inhibitors; D009498:Neurotoxins; D013792:Thalidomide; D017378:Quinolinic Acid