Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats

Zhang, Han‐Ting; Huang, Ying; Suvarna, Neesha U.; Deng, Chunhua; Crissman, Alicia M.; Hopper, Allen T.; Vivo, Michael De; Rose, Gregory M.; O’Donnell, James M.

doi:10.1007/s00213-004-2085-2

Cited by 77 publications

(68 citation statements)

References 29 publications

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“…While overall inhibition of PDE4 enhances memory performance in animals (Barad et al, 1998;Zhang et al, 2004Zhang et al, , 2005, PDE4BÀ/À mice did not show significant changes in either short-or long-term memory in step-down passive avoidance and Morris water-maze tasks (Table 1 and Figure 5), two tests measuring hippocampus-based memory (Bevilaqua et al, 1997). This is consistent with the limited expression of PDE4B in the hippocampus (Cherry and Davis, 1999).…”

Section: Pde4b-deficiency and Behavior H-t Zhang Et Alsupporting

confidence: 75%

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Zhang

Huang

Masood

et al. 2007

Neuropsychopharmacol

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158

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Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression-and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4BÀ/À). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4BÀ/À mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4BÀ/À mice. Compared to PDE4B + / + littermates, PDE4BÀ/À mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light-dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4BÀ/À mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4BÀ/À mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4BÀ/À mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior.

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Section: Pde4b-deficiency and Behavior H-t Zhang Et Alsupporting

confidence: 75%

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Zhang

Huang

Masood

et al. 2007

Neuropsychopharmacol

Self Cite

158

143

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“…98 It has also been shown that Dunce mutants have altered axonal growth cone motility, 99 neuronal function 100,101 and synaptic plasticity. 102 The PDE4 inhibitors MEM1018 and MEM1091 influence NMDA receptor-dependent memory, 103 and other selective PDE4 inhibitors including rolipram have been shown to influence memory and cognition in several studies. [103][104][105][106][107][108][109][110] Moreover, translation of specific PDE4 isoforms is regulated during long-term potentiation 111 and in NMDA-receptor-mediated memory functions.…”

Section: Pde4b As a Risk Factor For Psychiatric Illness: Interaction mentioning

confidence: 99%

“…102 The PDE4 inhibitors MEM1018 and MEM1091 influence NMDA receptor-dependent memory, 103 and other selective PDE4 inhibitors including rolipram have been shown to influence memory and cognition in several studies. [103][104][105][106][107][108][109][110] Moreover, translation of specific PDE4 isoforms is regulated during long-term potentiation 111 and in NMDA-receptor-mediated memory functions. 112 PDE4s also influence myelination, 113 and rolipram has been shown to reduce demyelination and CNS inflammation, 114 and to promote axon regrowth and myelination in vivo.…”

Section: Pde4b As a Risk Factor For Psychiatric Illness: Interaction mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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“…MEM1018 and MEM1091 are PDE4 inhibitors that behave much like rolipram with comparable PDE4 inhibitory activity profiles. MEM1018, MEM1091, and rolipram can restore pharmacologically induced impairment of long term memory and potentiate NMDAstimulated cAMP production (Zhang, Huang et al 2005). Based on the cAMP theory, pharmacotherapies modulating the cAMP cascade have potential as both a nootropic to improve mnemonic processing and an anxiolytic.…”

Section: Camp Therapymentioning

confidence: 99%

The cyclic AMP phenotype of fragile X and autism

Kelley

Bhattacharyya

Lahvis

et al. 2008

Neuroscience & Biobehavioral Reviews

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Cyclic AMP (cAMP) is a second messenger involved in many processes including mnemonic processing and anxiety. Memory deficits and anxiety are noted in the phenotype of fragile X (FX), the most common heritable cause of mental retardation and autism. Here we review reported observations of altered cAMP cascade function in FX and autism. Cyclic AMP is a potentially useful biochemical marker to distinguish autism comorbid with FX from autism per se and the cAMP cascade may be a viable therapeutic target for both FX and autism.

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Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats

Abstract: The novel PDE4 inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 inhibitors in the mediation of memory.

Cited by 77 publications

References 29 publications

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

The DISC locus in psychiatric illness

The cyclic AMP phenotype of fragile X and autism

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