CNS penetration of small molecules following local inflammation, widespread systemic inflammation or direct injury to the nervous system.
OBJECTIVE
We sought to investigate effects of local and systemic inflammation on CNS permeability of small molecules and compare these to effects of direct injury to the nervous system.


METHODS
Evans blue was used to determine the integrity of the blood-brain barrier (BBB) following local inflammation, systemic inflammation, injury to the L5 spinal nerve or transient occlusion of the middle cerebral artery. In addition, three compounds having low, medium and high brain permeability (atenolol, morphine and oxycodone, respectively) were used. Following model establishment (4-hr post-carrageenan, 24-hr post-FCA, 2-, 4- and 24-hr post-LPS, 21 days post-nerve injury) compounds were administered and 30 min later the brain, spinal cord and blood removed. The plasma and tissue concentrations of compounds were quantified by LC/MS/MS.


RESULTS
Localized inflammation did not affect Evans blue penetration into the CNS but significantly increased morphine penetration into the spinal cord. Systemic inflammation increased the quantity of Evans blue in the CNS but also decreased the penetration of atenolol, morphine and oxycodone into the brain 4-hr post-insult. Nerve injury had no effect on Evans blue or compound penetration, while middle cerebral artery occlusion resulted in a large but short lived increase in Evans blue penetration into both the cortex and striatum.


CONCLUSIONS
The presence of inflammation may affect the CNS penetration of some compounds but is unlikely to lead to a large non-selective BBB breakdown. As a result, it is appropriate to test for side-effects, and conduct brain pharmacokinetic determinations, in naïve rats.
Lu
Peimin
P
Neuroscience Discovery Research, Wyeth Research, CN8000, Princeton, NJ 08543, USA.
Gonzales
Cathy
C
Chen
Yi
Y
Adedoyin
Adedayo
A
Hummel
Michele
M
Kennedy
Jeffrey D
JD
Whiteside
Garth T
GT
D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism; D001262:Atenolol / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002351:Carrageenan; D002490:Central Nervous System / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D005620:Freund's Adjuvant; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology; D009020:Morphine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013127:Spinal Nerves / Q000293:injuries / Q000473:pathology
D000319:Adrenergic beta-Antagonists; D008070:Lipopolysaccharides; D001262:Atenolol; D009020:Morphine; D002351:Carrageenan; D005620:Freund's Adjuvant