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Therapeutic utility of phosphodiesterase type I inhibitors in neurological conditions.

Medina AE - Front Neurosci (2011)

Bottom Line: Neuronal plasticity is an essential property of the brain that is impaired in different neurological conditions.Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules.However, the lack of specificity of the drugs currently available poses a challenge to the systematic evaluation of the beneficial effect of these agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center Richmond, VA, USA.

ABSTRACT
Neuronal plasticity is an essential property of the brain that is impaired in different neurological conditions. Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. These neuronal plasticity enhancement properties make PDE1 inhibitors good candidates as therapeutic agents in many neurological conditions. However, the lack of specificity of the drugs currently available poses a challenge to the systematic evaluation of the beneficial effect of these agents. The development of more specific drugs may pave the way for the use of PDE1 inhibitors as therapeutic agents in cases of neurodevelopmental conditions such as fetal alcohol spectrum disorders and in degenerative disorders such as Alzheimer's and Parkinson's.

No MeSH data available.


Related in: MedlinePlus

Inhibition of phosphodiesterase type 1 may lead to phosphorylation of AMPA receptors and its incorporation to the synapse. AC, adenyl cyclase; GC, guanylate cyclase.
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Figure 2: Inhibition of phosphodiesterase type 1 may lead to phosphorylation of AMPA receptors and its incorporation to the synapse. AC, adenyl cyclase; GC, guanylate cyclase.

Mentions: Another way that PDE inhibition can improve neuronal plasticity is trough potentiation of glutamatergic transmission (Figure 2). The increase in cAMP/cGMP levels caused by PDE1 inhibition, can lead to the phosphorylation of AMPA receptors promoting its incorporation into the synapse (Serulle et al., 2007) and leading to facilitation of the glutamatergic transmission. AMPA receptors can move in and out the synaptic membrane affecting glutamatergic transmission by making NMDA receptors functional (Malinow and Malenka, 2002). At the resting membrane potential, the NMDA receptor is blocked by Mg++ (Mayer et al., 1984; Nowak et al., 1984). However, activation of AMPA receptors can depolarize the postsynaptic membrane, releasing the Mg++ blockade and making the NMDA receptor functional (Mayer et al., 1984; Nowak et al., 1984). Therefore, NMDA receptor activation can be facilitated or reduced respectively by insertion/removal of AMPA receptors in/from the postsynaptic membrane (Malinow and Malenka, 2002; Malenka and Bear, 2004).


Therapeutic utility of phosphodiesterase type I inhibitors in neurological conditions.

Medina AE - Front Neurosci (2011)

Inhibition of phosphodiesterase type 1 may lead to phosphorylation of AMPA receptors and its incorporation to the synapse. AC, adenyl cyclase; GC, guanylate cyclase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3044262&req=5

Figure 2: Inhibition of phosphodiesterase type 1 may lead to phosphorylation of AMPA receptors and its incorporation to the synapse. AC, adenyl cyclase; GC, guanylate cyclase.
Mentions: Another way that PDE inhibition can improve neuronal plasticity is trough potentiation of glutamatergic transmission (Figure 2). The increase in cAMP/cGMP levels caused by PDE1 inhibition, can lead to the phosphorylation of AMPA receptors promoting its incorporation into the synapse (Serulle et al., 2007) and leading to facilitation of the glutamatergic transmission. AMPA receptors can move in and out the synaptic membrane affecting glutamatergic transmission by making NMDA receptors functional (Malinow and Malenka, 2002). At the resting membrane potential, the NMDA receptor is blocked by Mg++ (Mayer et al., 1984; Nowak et al., 1984). However, activation of AMPA receptors can depolarize the postsynaptic membrane, releasing the Mg++ blockade and making the NMDA receptor functional (Mayer et al., 1984; Nowak et al., 1984). Therefore, NMDA receptor activation can be facilitated or reduced respectively by insertion/removal of AMPA receptors in/from the postsynaptic membrane (Malinow and Malenka, 2002; Malenka and Bear, 2004).

Bottom Line: Neuronal plasticity is an essential property of the brain that is impaired in different neurological conditions.Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules.However, the lack of specificity of the drugs currently available poses a challenge to the systematic evaluation of the beneficial effect of these agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center Richmond, VA, USA.

ABSTRACT
Neuronal plasticity is an essential property of the brain that is impaired in different neurological conditions. Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. These neuronal plasticity enhancement properties make PDE1 inhibitors good candidates as therapeutic agents in many neurological conditions. However, the lack of specificity of the drugs currently available poses a challenge to the systematic evaluation of the beneficial effect of these agents. The development of more specific drugs may pave the way for the use of PDE1 inhibitors as therapeutic agents in cases of neurodevelopmental conditions such as fetal alcohol spectrum disorders and in degenerative disorders such as Alzheimer's and Parkinson's.

No MeSH data available.


Related in: MedlinePlus