Caffeine protects against MPTP-induced blood-brain barrier dysfunction in mouse striatum.
The blood-brain barrier (BBB) is important physiologically. Pathologically, BBB disruption has been implicated in a wide spectrum of neurological disorders including Parkinson's disease (PD). Recent studies indicate that caffeine is protective against PD, but by poorly understood mechanisms. Using a MPTP neurotoxin model of PD we tested the hypothesis that the protective actions of caffeine were because of, at least in part, preventing MPTP-induced BBB dysfunction. FVB mice were pre-treated with caffeine (10 mg/kg, i.p.) or saline for 7 days prior to initiation of neurotoxin treatments; during the 7 days of neurotoxin treatment, caffeine or saline continued to be administered 10 min before each dose of MPTP (20 mg/kg, i.p.). Striatum (and for some studies hippocampus and cerebral cortex as well) were evaluated for BBB leakage, tight junction protein expression levels, integrity of dopaminergic neurons, and activation of astrocytes and microglia using immunostaining, immunoblotting and real-time PCR techniques. We found that caffeine blocked MPTP-induced decreases in numbers of tyrosine hydroxylase-positive dopaminergic neurons, increases in leakage of Evan's blue dye and FITC-albumin in striatum but not in cerebral cortex or hippocampus, decreases in levels of the tight junction proteins occludin and ZO-1, and increases in reactive gliosis. Our results suggest that caffeine might protect against PD and PD-like features in animal models, in part, by stabilizing the BBB.
Chen
Xuesong
X
Department of Pharmacology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58203, USA.
Lan
Xun
X
Roche
Ian
I
Liu
Rugao
R
Geiger
Jonathan D
JD
D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005070:Evans Blue; D005786:Gene Expression Regulation / Q000187:drug effects; D005911:Gliosis / Q000139:chemically induced / Q000517:prevention & control; D020267:MPTP Poisoning / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
D000697:Central Nervous System Stimulants; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D002110:Caffeine; D005070:Evans Blue; D014446:Tyrosine 3-Monooxygenase; D020780:Matrix Metalloproteinase 9