Gong B, Vitolo OV, Trinchese F, Liu S, Shelanski M, Arancio O.
Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment.
J Clin Invest. 2004 Dec;114(11):1624-34.
PubMed.
Arancio, first author Bing Gong, and colleagues show evidence that Rolipram improved synaptic and cognitive functions in an Alzheimer mouse model. The cAMP/PKA/CREB pathway controls CREB-dependent gene expression, which is fundamental for neuronal survival, and plasticity involved in memory process—all affected in AD. Several groups have previously reported that abnormal β-amyloid accumulation induces cognitive impairment that parallels disturbances in cAMP signaling, including a decrease in PKA and CREB activation. β amyloid-induced inhibition of the PKA/CREB pathway and long-term potentiation (a cellular model of learning) seem to be rescued by drugs that enhance cAMP signaling (Vitolo et al., 2002). In concurrence with this evidence, we reported in NSF and at the ADRD meeting that stimulation of the PGE2 EP2 receptor, which increases cAMP levels, protected cultured cortical neurons against Aβ toxicity (Echeverria, V and Doré, S. 9th Intl. Conference on Alzheimer’s Disease and Related Disorders. 2004). Rolipram is a selective inhibitor of phosphodiesterase PDE4 and induces an elevation of intracellular cAMP and release of norepinephrine, enhancing central noradrenergic transmission, and suppressing expression of several mediators of inflammation. PDE4 is used to treat leukemia patients. From there we learned that some resistance to treatment with Rolipram can appear, because elevated cAMP levels can induce compensatory upregulation of other PDE families. Some combination therapy with more than one PDE4 inhibitor or use of dual-selective drugs may likely be of benefit in a subset of potentially PDE4-inhibitor-resistant patients and also directed to decrease Aβ levels. It is impressive that Rolipram could have these long-term benefits without decreasing the amyloid burden and Aβ levels. In this respect, it would be interesting to investigate if Rolipram reduces intracellular Aβ accumulation. The risk associated with the use of these PDE4 inhibitors in the elderly as well the advantages with respect to other PDE inhibitors such as caffeine need to be carefully evaluated. However, the benefits in terms of neuroprotection and anti-cancer properties made these kinds of PDE inhibitors promising therapeutic tools.
References:
Vitolo OV, Sant'Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M.
Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling.
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13217-21.
PubMed.
Comments
Bay pines VA Health care system
Arancio, first author Bing Gong, and colleagues show evidence that Rolipram improved synaptic and cognitive functions in an Alzheimer mouse model. The cAMP/PKA/CREB pathway controls CREB-dependent gene expression, which is fundamental for neuronal survival, and plasticity involved in memory process—all affected in AD. Several groups have previously reported that abnormal β-amyloid accumulation induces cognitive impairment that parallels disturbances in cAMP signaling, including a decrease in PKA and CREB activation. β amyloid-induced inhibition of the PKA/CREB pathway and long-term potentiation (a cellular model of learning) seem to be rescued by drugs that enhance cAMP signaling (Vitolo et al., 2002). In concurrence with this evidence, we reported in NSF and at the ADRD meeting that stimulation of the PGE2 EP2 receptor, which increases cAMP levels, protected cultured cortical neurons against Aβ toxicity (Echeverria, V and Doré, S. 9th Intl. Conference on Alzheimer’s Disease and Related Disorders. 2004). Rolipram is a selective inhibitor of phosphodiesterase PDE4 and induces an elevation of intracellular cAMP and release of norepinephrine, enhancing central noradrenergic transmission, and suppressing expression of several mediators of inflammation. PDE4 is used to treat leukemia patients. From there we learned that some resistance to treatment with Rolipram can appear, because elevated cAMP levels can induce compensatory upregulation of other PDE families. Some combination therapy with more than one PDE4 inhibitor or use of dual-selective drugs may likely be of benefit in a subset of potentially PDE4-inhibitor-resistant patients and also directed to decrease Aβ levels. It is impressive that Rolipram could have these long-term benefits without decreasing the amyloid burden and Aβ levels. In this respect, it would be interesting to investigate if Rolipram reduces intracellular Aβ accumulation. The risk associated with the use of these PDE4 inhibitors in the elderly as well the advantages with respect to other PDE inhibitors such as caffeine need to be carefully evaluated. However, the benefits in terms of neuroprotection and anti-cancer properties made these kinds of PDE inhibitors promising therapeutic tools.
References:
Vitolo OV, Sant'Angelo A, Costanzo V, Battaglia F, Arancio O, Shelanski M. Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13217-21. PubMed.
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