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Dose and chemical modification considerations for continuous cyclic AMP analog delivery to the injured CNS.
- Source :
-
Journal of neurotrauma [J Neurotrauma] 2009 May; Vol. 26 (5), pp. 733-40. - Publication Year :
- 2009
-
Abstract
- In this investigation, two cell-permeable synthetic analogs of cAMP, dibutyryl-cAMP (db-cAMP) and 8-bromo-cAMP, which are widely used to elevate intracellular cAMP levels under experimental conditions, were investigated for their ability to dose-dependently improve histological and functional outcomes following continuous delivery in two models of incomplete spinal cord injury (SCI). The cAMP analogs were delivered via osmotic minipumps at 1-250 mM through an indwelling cortical cannula or by intrathecal infusion for up to 4 weeks after either a T8 unilateral over-hemisection or a C2-3 dorsolateral quadrant lesion, respectively. In both SCI models, continuous db-cAMP delivery was associated with histopathological changes that included sporadic micro-hemorrhage formation and cavitation, enhanced macrophage infiltration and tissue damage at regions beyond the immediate application site; no deleterious or beneficial effect of agent delivery was observed at the spinal injury site. Furthermore, these changes were accompanied by pronounced behavioral deficits that included an absence of progressive locomotor recovery, increased extensor tone, paralysis, and sensory abnormalities. These deleterious effects were not observed in saline-treated animals, in animals in which the db-cAMP dose did not exceed 1 mM, or in those animals that received a high dose (250 mM) of the alternative cAMP analog, 8-bromo-cAMP. These results demonstrate that, for continuous intraparenchymal or intrathecal administration of cAMP analogs for the study of biological or therapeutic effects within the central nervous system (CNS), consideration of the effective concentration applied as well as the potential toxicity of chemical moieties on the parent molecule and/or their activity needs to be taken into account.
- Subjects :
- Animals
Axons pathology
Behavior, Animal physiology
Cerebral Cortex metabolism
Contusions drug therapy
Dose-Response Relationship, Drug
Female
Immunohistochemistry
Infusion Pumps, Implantable
Injections, Spinal
Locomotion physiology
Macrophages pathology
Rats
Rats, Inbred Lew
Spinal Cord pathology
Spinal Cord Injuries pathology
Spinal Cord Injuries psychology
8-Bromo Cyclic Adenosine Monophosphate administration & dosage
8-Bromo Cyclic Adenosine Monophosphate therapeutic use
Bucladesine administration & dosage
Bucladesine therapeutic use
Spinal Cord Injuries drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1557-9042
- Volume :
- 26
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of neurotrauma
- Publication Type :
- Academic Journal
- Accession number :
- 19397425
- Full Text :
- https://doi.org/10.1089/neu.2008.0730