The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery
346
Citation
35
Reference
10
Related Paper
Citation Trend
Abstract:
Although there is no spontaneous regeneration of mammalian spinal axons after injury, they can be enticed to grow if cAMP is elevated in the neuronal cell bodies before the spinal axons are cut. Prophylactic injection of cAMP, however, is useless as therapy for spinal injuries. We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood–brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo . Two weeks after a hemisection lesion at C3/4, with embryonic spinal tissue implanted immediately at the lesion site, a 10-day delivery of rolipram results in considerable axon regrowth into the transplant and a significant improvement in motor function. Surprisingly, in rolipram-treated animals, there was also an attenuation of reactive gliosis. Hence, because rolipram promotes axon regeneration, attenuates the formation of the glial scar, and significantly enhances functional recovery, and because it is effective when delivered s.c., as well as post-injury, it is a strong candidate as a useful therapy subsequent to spinal cord injury.Keywords:
Rolipram
Gliosis
Glial scar
Abstract The effects of nine cAMP‐phosphodiesterase inhibitors, including amrinone, milrinone, enoximone, piroximone, imazodan (Cl‐914), CK‐2438 (4,5‐dihydro‐6‐[pyridin‐4‐yl]‐3‐[2H]pyridazinone), rolipram, ZK‐73433 4[(3,4‐dimethoxy‐phenyl)methyl]‐2‐pyrolidinone), and IBMX (3‐isobutyl‐1‐methylxanthine) were determined on crude enzyme fractions prepared from heart, brain, and thoracic aorta of dogs. Inhibitors, such as amrinone, milrinone, enoximone, piroximone, imazodan, and CK‐2438, were found to be specific for the enzyme from the heart, but not that from the brain and thoracic aorta. On the other hand, rolipram and ZK‐73433 were potent inhibitors of the brain enzyme, but not of enzymes from the heart and thoracic aorta. None of these compounds effectively depressed cGMP‐phosphodiesterase from the thoracic aorta. Conversely, IBMX was nonspecific because it was equally active on the cAMP‐phosphodiesterases from all three tissues and the cGMP‐phosphodiesterase from the thoracic aorta. The abilities of these compounds to inhibit the cAMP‐phosphodiesterase from the three tisses were not a function of their different lipid solubilities. It is concluded that most inhibitors exhibited tissue specificity on the cAMP‐phosphodiesterases from various organs of one animal species. These data also suggest the existence of isoforms of cAMP‐phosphodiesterase (PDE‐III) in different tissues.
Rolipram
Milrinone
Enoximone
Amrinone
IBMX
Phosphodiesterase 3
PDE10A
Cite
Citations (12)
Several previous studies have demonstrated that the phosphodiesterase 4 selective inhibitor rolipram affects cellular function at a much lower concentration than the reported Ki value for phosphodiesterase 4 inhibition. In this study, we examined the inhibitory effect of rolipram on rat brain phosphodiesterase 4 to determine the heterogeneity of the enzyme activity. Partial purification of various phosphodiesterases from the rat brain was performed by anion-exchange chromatography. The eluant was pooled into four fractions, two of which manifested cAMP-selective phosphodiesterase activity that was blocked by 10 microM of rolipram, indicating the presence of phosphodiesterase 4 in these fractions. The IC50 of rolipram (racemate) of these two fractions was 492 and 79 nM, respectively. The R-(-)-enantiomer of rolipram inhibited the cAMP-phosphodiesterase activity in the latter fraction 10 times more than did S-(+)-rolipram, and the inhibition of the former fraction was less stereospecific. Dixon plot analysis revealed that the rolipram enantiomers inhibited the cAMP-phosphodiesterase in the latter fraction in a multiphasic manner, with two Ki values, one at the micromolar level and the other at the sub-micromolar level, respectively, for both of the enantiomers. These results suggest that there is a heterogeneity for phosphodiesterase 4 in the rat brain, and some of the phosphodiesterase forms are sensitive to rolipram.
Rolipram
IC50
Cite
Citations (7)
Rolipram
HEK 293 cells
Cyclic nucleotide phosphodiesterase
PDE10A
Phosphodiesterase 3
Cite
Citations (29)
Background and purpose: Phosphodiesterase (PDE) inhibitors are useful to treat hypoxia‐related diseases and are used in experiments studying the effects of oxygen on 3′‐5′‐cyclic adenosine monophosphate (cAMP) production. We studied the effects of acute hypoxia on cAMP accumulation induced by PDE inhibitors in oxygen‐specific chemosensors, the carotid bodies (CBs) and in non‐chemosensitive CB‐related structures: carotid arteries (CAs) and superior cervical ganglia (SCG). Experimental approach: Concentration–response curves for the effects of a non‐specific PDE inhibitor [isobutylmethylxanthine (IBMX) ], PDE4 selective inhibitors (rolipram, Ro 20‐1724) and a PDE2 selective inhibitor (erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine) on cAMP levels were obtained in normoxic (20% O 2 /5% CO 2 ) or hypoxic (5% O 2 /5% CO 2 ) conditions. Key results: Responses to the PDE inhibitors were compatible with the presence of PDE4 in rat CBs, CAs and SCG but in the absence of PDE2 in CAs and CBs. Acute hypoxia enhanced the effects of IBMX and PDE4 inhibitors on cAMP accumulation in CAs and CBs. In SCG, acute hypoxia reduced cAMP accumulation induced by all the four PDE inhibitors tested. Differences between the effects of Ro 20‐1724 and rolipram on cAMP were found in CAs and CBs during hypoxia. Conclusions and implications: The effects of PDE4 inhibitors could be potentiated or inhibited by acute hypoxia depending on the PDE isoforms of the tissue. The similarities between the characterization of PDE4 inhibitors at the CBs and CAs, under normoxia and hypoxia, did not support a specific role for cAMP in the oxygen‐sensing machinery at the CB and suggested that no direct CB‐mediated, hyperventilatory, adverse effects would be expected with administration of PDE4 inhibitors.
Rolipram
IBMX
Hypoxia
Phosphodiesterase inhibitor
PDE10A
Cite
Citations (15)
Rolipram
Modulation (music)
PDE10A
Cite
Citations (33)
Rolipram
Cyclic nucleotide phosphodiesterase
PDE10A
Thymocyte
Phosphodiesterase 3
Cite
Citations (39)
Rolipram
Phosphodiesterase 3
Roflumilast
Cite
Citations (16)
Rolipram
PDE10A
Second messenger system
Phosphodiesterase 3
Cite
Citations (0)
Rolipram
Zaprinast
PDE10A
Cyclic nucleotide phosphodiesterase
Cite
Citations (20)
Rolipram
PDE10A
Phosphodiesterase 3
Phosphodiesterase inhibitor
Cite
Citations (26)