Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterase 10A (PDE10A) is a recently identified cyclic nucleotide phosphodiesterase expressed primarily in dopaminoreceptive medium spiny neurons of the striatum. We report that papaverine is a potent, specific inhibitor of PDE10A and use this compound to explore the role of PDE10A in regulating striatal function. Papaverine administration produces an increase in striatal tissue levels of cGMP and an increase in extracellular cAMP measured by microdialysis. These cyclic nucleotide changes are accompanied by increases in the phosphorylation of CREB and ERK, downstream markers of neuronal activation. In rats, papaverine potentiates haloperidol-induced catalepsy, consistent with the hypothesis that inhibition of PDE10A can increase striatal output and prompting a further evaluation of papaverine in models predictive of antipsychotic activity. Papaverine is found to inhibit conditioned avoidance responding in rats and mice and to inhibit PCP- and amphetamine-stimulated locomotor activity in rats. The effects of papaverine on striatal cGMP and CREB and ERK phosphorylation, as well as on conditioned avoidance responding, were absent in PDE10A knockout mice, indicating that the effects of the compound are the result of PDE10A inhibition. These results indicate that PDE10A regulates the activation of striatal medium spiny neurons through effects on cAMP- and cGMP-dependent signaling cascades. Furthermore, the present results demonstrate that papaverine has efficacy in behavioral models predictive of antipsychotic activity. Thus, inhibition of PDE10A may represent a novel approach to the treatment of psychosis.
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PMID:Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. 1678 Aug 99

The phosphodiesterase 10A (PDE10A) is highly expressed within dopaminoreceptive medium spiny neurons (MSNs) of the striatum, which are implicated in various neurodegenerative diseases and psychiatric disorders, such as Huntington's disease and schizophrenia. With its dual action on cAMP and cGMP, PDE10A has been proposed to affect several signaling cascades in the corticostriatothalamic circuits. In particular, papaverine, a selective PDE10A inhibitor has been shown to activate/phosphorylate ERK in striatum. We used acute rat striatal slices to further characterize the effects of papaverine on ERK activation/phosphorylation in D1- and D2-responsive striatal neurons. Incubation of striatal slices from male rats with papaverine increased the levels of phospho-ERK1/2 (p-ERK), an effect enhanced with a D1 agonist or a D2 antagonist, but decreased with a D1 receptor antagonist or a D2 receptor agonist. Papaverine-induced increase in p-ERK was localized in striatal neurons receiving D1-enriched presynaptic terminals, as well as in postsynaptic D2-enriched neurons in striatal slices. Interestingly, papaverine had almost no stimulatory effects on ERK1/2 phosphorylation in slices prepared from female rats. In striatal slices prepared from ovariectomized female rats, papaverine treatment stimulated ERK1/2 phosphorylation to levels similar to those in slices from male rats. Moreover, estrogen was found to regulate the levels of D2 but not D1 receptors in striatum. These results indicate that circulating levels of female hormones, and in particular estrogen, regulate the effects of PDE10A inhibition on ERK1/2 phosphorylation in medium spiny neurons, an effect possibly linked to estrogen's regulation of D2 receptors. Considering the variety of events modulated by ERK1/2 activity, these findings suggest that sex difference needs to be taken into consideration for the further investigation of the effects of PDE10A inhibitors.
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PMID:The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices. 2181 64

Traumatic brain injury (TBI) contributes to morbidity in children, and boys are disproportionately represented. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Cerebral perfusion pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP). In prior studies of 1- to 5-day-old newborn piglets, we observed that norepinephrine (NE) preferentially protected cerebral autoregulation and prevented hippocampal necrosis in females but not males after fluid percussion injury (FPI). The ERK isoform of mitogen activated protein kinase (MAPK) produces hemodynamic impairment after FPI, but less is known about the role of the cytokine interleukin-6 (IL-6). We investigated whether NE protects autoregulation and limits histopathology after FPI in older juvenile (4-week-old) pigs and the role of ERK and IL-6 in that outcome by sex. Results show that NE significantly protects autoregulation and prevents reduction in cerebral blood flow (CBF) in both male and female juvenile pigs after FPI; co-administration of the ERK antagonist U 0126 with NE fully protects both indices of outcome. Papaverine induced dilation was unchanged by FPI and NE. NE blunted ERK MAPK and IL-6 upregulation in both males and females after FPI. NE attenuated loss of neurons in CA1 and CA3 hippocampus of males and females after FPI. These data indicate that NE protects autoregulation and limits hippocampal neuronal cell necrosis via blockade of ERK and IL-6 after FPI in both male and female juvenile pigs. These data suggest that use of NE to improve outcome after TBI is both sex and age dependent.
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PMID:Norepinephrine Protects Cerebral Autoregulation and Reduces Hippocampal Necrosis after Traumatic Brain Injury via Blockade of ERK MAPK and IL-6 in Juvenile Pigs. 2659 84

Traumatic brain injury (TBI) contributes to morbidity in children, and more boys experience TBI. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Cerebral Perfusion Pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP). In prior studies of newborn and juvenile pigs, vasoactive agent choice influenced outcome after TBI as a function of age and sex, with none protecting cerebral autoregulation in both ages and sexes. Dopamine (DA) prevents impairment of cerebral autoregulation in male and female newborn pigs via inhibition of upregulation of ERK mitogen activated protein kinase (MAPK) after fluid percussion injury (FPI). We investigated whether DA protects autoregulation and limits histopathology after FPI in juvenile pigs and the role of ERK in that outcome. Results show that DA protects autoregulation in both male and female juvenile pigs after FPI. Papaverine induced dilation was unchanged by FPI and DA. DA blunted ERK MAPK and prevented loss of neurons in CA1 and CA3 hippocampus of males and females after FPI. These data indicate that DA protects autoregulation and limits hippocampal neuronal cell necrosis via block of ERK after FPI in male and female juvenile pigs. Of the vasoactive agents prior investigated, including norepinephrine, epinephrine, and phenylephrine, DA is the only one demonstrated to improve outcome after TBI in both sexes and ages. These data suggest that DA should be considered as a first line treatment to protect cerebral autoregulation and promote cerebral outcomes in pediatric TBI irrespective of age and sex.
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PMID:Dopamine protects cerebral autoregulation and prevents hippocampal necrosis after traumatic brain injury via block of ERK MAPK in juvenile pigs. 2862 90