Activation of tyrosine hydroxylase prevents pneumonia in a rat chronic cerebral hypoperfusion model.
Pneumonia is a common complication with the highest attributable proportion of deaths in patients with stroke. Cilostazol is a potent type III phosphodiesterase inhibitor, approved as an anti-platelet aggregation agent. The present study was designed to determine the protective mechanism of cilostazol against post-stroke pneumonia using a rat chronic cerebral hypoperfusion model. Rats were subjected to bilateral common carotid artery ligation (LBCCA) and divided randomly into the vehicle group (n=72) and cilostazol group (n=72). Rats of each group were sacrificed at baseline and at days 14, 28 and 42 after LBCCA. Cilostazol significantly improved the swallowing reflex by shortening the latency to elicited swallowing and increasing the numbers of swallows (P<0.05) at 14 days of hypoperfusion. It also decreased the numbers of bacterial colonies grown in cultures from homogenized lungs. Cilostazol markedly upregulated cyclic AMP responsive element binding protein (CREB) phosphorylation, increased tyrosine hydroxylase (TH) expression in the substantial nigra, and maintained dopamine (84.7+/-2.3 vs. 79.2+/-4.1% control; P=0.0512) and substance P levels (86.6+/-7.9 vs. 73.9+/-6.5% control; P<0.05) in the striatum, compared with the vehicle group. Our results indicate that cilostazol improves the swallowing reflex by enhancing the expression of TH through the CREB phosphorylation signaling pathway, and suggest that cilostazol could be useful in preventing pneumonia in the chronic stage of stroke.
Zhang
N
N
Research Institute for Disease of Old Age, Japan.
Miyamoto
N
N
Tanaka
R
R
Mochizuki
H
H
Hattori
N
N
Urabe
T
T
D000818:Animals; D001419:Bacteria / Q000187:drug effects; D016893:Carotid Stenosis / Q000150:complications / Q000209:etiology; D002908:Chronic Disease; D000077407:Cilostazol; D003342:Corpus Striatum / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003679:Deglutition / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008026:Ligation / Q000379:methods; D008297:Male; D011014:Pneumonia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D013373:Substance P / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D005343:Fibrinolytic Agents; D013777:Tetrazoles; D013373:Substance P; D014446:Tyrosine 3-Monooxygenase; D000077407:Cilostazol; D004298:Dopamine