CHRONIC NICOTINE TREATMENT ENHANCES FOCAL ISCHEMIC BRAIN INJURY AND DEPLETES FREE POOL OF BRAIN MICROVASCULAR TISSUE-PLASMINOGEN ACTIVATOR IN RATS

Effects of nicotine treatment (4.5 mg/kg of nicotine-free base/day adm inistered s.c. by osmotic minipumps for 14 days) on focal ischemic str oke and expression of tissue plasminogen activator (t-PA) and plasmino gen activator inhibitor-1 (PAI-1) in cerebral microvessels were studie d in rats in vivo using a reversible (1 h) middle cerebral artery occl usion model. Plasma levels of nicotine and its major metabolite cotini ne after 14 days of treatment were 88 and 364 ng/ml, respectively. Nic otine treatment resulted in 35-40% (p <0.001) decrease in the blood fl ow in the periphery of the ischemic core during reperfusion, an increa se in the neurologic score of 2.6-fold (p <0.01), and 36% (p <0.05) an d 121% (p <0.01) increases in the injury and edema volume in the palli um, respectively. A free pool of brain microvascular t-PA antigen was completely depleted by nicotine, while the expression of the PAI-1 ant igen and/or PAI-1-t-PA complexes remained unchanged. The relative abun dance of cerebromicrovascular t-PA mRNA transcript versus beta-actin m RNA transcript did not change with nicotine. It is concluded that chro nic nicotine treatment impairs the restoration of blood flow, worsens the neurologic outcome, and enhances brain injury following an ischemi c insult. These nicotine effects are associated with depletion of brai n microvascular t-PA antigen.