Effects of Repeated Treatment with Phosphodiesterase-4 Inhibitors on cAMP Signaling, Hippocampal Cell Proliferation, and Behavior in the Forced-Swim Test

Abstract

The effects of repeated treatment with the phosphodiesterase-4 (PDE4) inhibitors rolipram, piclamilast, and 4-(2-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-phenylethyl)pyridine (CDP840), which differ in their interactions with high-and low-affinity binding conformers of the enzyme, were contrasted to those of acute treatment on cAMP signaling, hippocampal cell proliferation, and immobility in the forced-swim test in rats. Repeated treatment with rolipram (1 and 3 mg/kg), piclamilast (0.3 and 1 mg/kg), or CDP840 (10 and 30 mg/kg) for 16 days increased cAMP and phosphorylation of cAMP response element binding protein (pCREB) in hippocampus and prefrontal cortex. In addition, repeated treatment with the PDE4 inhibitors increased proliferation and survival of newborn cells in the hippocampus and produced antidepressant-like effects on behavior, as evidenced by decreased immobility in the forced-swim test. Acute treatment with rolipram (3 mg/kg), piclamilast (1 mg/kg), or CDP840 (30 mg/kg) induced transient increases in cAMP and pCREB in hippocampus and prefrontal cortex, but the dose and time dependence of these effects did not parallel the behavioral effects. Compared with rolipram and piclamilast, repeated treatment with CDP840 exerted lesser effects on neural and behavioral measures, probably because of its weak interaction with the high-affinity binding conformer of PDE4. This suggests the relative importance of the high-affinity binding conformer in the mediation of the long-term effects of PDE4 inhibition on cAMP/pCREB signaling, hippocampal cell proliferation, and antidepressant-like effects on behavior.

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

“…Then, pharmacological modulation of the Ca 2+ /cAMP signalling interaction could be a new therapeutic strategy to treat neurological and psychiatric disorders resulting from neurotransmitter release deficit. In addition, pharmacological modulation of the Ca 2+ /cAMP signalling interaction could reduce neuronal death in neurodegenerative disease due to attenuation of cytosolic Ca 2+ overload, increase of [cAMP]c and stimulation of cell survival pathways mediated by CREB [22][23][24]. Thus, pharmacological modulation of Ca 2+ /cAMP signalling interaction could be a new neuroprotective therapeutic strategy to slow the progression of neurodegenerative diseases, such as AD [5][6][7][8]25,26].…”

“…/cAMP signalling interaction regulates various cellular responses, including neurotransmitter release [5][6][7][8]. Many studies showed that increase of [cAMP]c stimulates neuroprotective response attenuating neuronal death due probably to activation of cellular survival pathways mediated by cAMP-response element binding protein (CREB) [22][23][24]. In this way, pharmacological modulation of the Ca 2+ /cAMP signalling interaction by combined use of L-type CCBs and cAMP-enhancer compounds could stimulate neuroprotective response due to increase of [cAMP]c and attenuation of cytosolic Ca 2+ overload [5][6][7][8].…”

Emerging Concepts for Neuroscience Field from Ca2+/ cAMP Signalling Interaction

“…Indeed, many reports have shown that increase of cytosolic cAMP concentration ([cAMP]c) stimulates neuroprotective effects [13,14]. Thus, elevating [cAMP]c by handling Ca 2+ /cAMP signalling interaction could reduce neuronal death triggered by cytosolic Ca 2+ overload [8][9][10][11].…”

Novel Challenges for the Therapeutics of Depression: Pharmacological Modulation of Interaction between the Intracellular Signaling Pathways Mediated by Ca2+ and cAMP

“…Recent studies have showed that chronic treatment with rolipram, together with typical antidepressants has been successful in the reduction of depression symptoms due to potentiation of these antidepressants effects [26]. Considering our model in which increment of [cAMP]c stimulates Ca 2+ release from ER (Figure 1), it may be plausible that the therapeutic use of the PDE inhibitor rolipram [27,28], in combination with low doses of verapamil to potentiate neurotransmission (Figure 1) in the areas of central nervous system involved in neurological/psychiatric disorders in which neurotransmission is reduced, including depression. This new pharmacological strategy for the treatment of psychiatric disorders could increase the therapeutic ef icacy and reduce the adverse effects of the medicines currently used for treating depression.…”