Dose and chemical modification considerations for continuous cyclic AMP analog delivery to the injured CNS.

Karim Fouad, Mousumi Ghosh, Romana Vavrek, Arthur D. Tse, Damien D Pearse

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)733-740
Number of pages8
JournalJournal of Neurotrauma
Volume26
Issue number5
StatePublished - May 1 2009
Externally publishedYes

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Cyclic AMP
8-Bromo Cyclic Adenosine Monophosphate
Central Nervous System
Spinal Cord Injuries
Artificial Cells
Spinal Injuries
Therapeutic Uses
Paralysis
Macrophages
Hemorrhage
Cannula

ASJC Scopus subject areas

  • Clinical Neurology

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Dose and chemical modification considerations for continuous cyclic AMP analog delivery to the injured CNS. / Fouad, Karim; Ghosh, Mousumi; Vavrek, Romana; Tse, Arthur D.; Pearse, Damien D.

In: Journal of Neurotrauma, Vol. 26, No. 5, 01.05.2009, p. 733-740.

Research output: Contribution to journalArticle

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