Differential and Brain Region–Specific Regulation of Rap-1 and Epac in Depressed Suicide Victims

Dwivedi, Yogesh K.; Mondal, Amal Chandra; Rizavi, Hooriyah S.; Faludi, Gábor; Palkovits, Miklós; Sárosi, Andrea; Conley, Robert R.; Pandey, Ghanshyam N.

doi:10.1001/archpsyc.63.6.639

Cited by 44 publications

(39 citation statements)

References 64 publications

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“…In addition, it is likely that compounds to modulate the levels of expression and function of the KLF11-MAO-mediated pathway may increase neuroprotection, neuroplasticity, and synaptic activities. Maximizing the therapeutic effects upon these targets is also essential toward achieving comprehensive management of stress-induced, frequently treatmentresistant, psychiatric illnesses, and addictions (Barr et al, 2004;Beasley et al, 2005;Dwivedi et al, 2006;Frazer, 1997;Mitchell et al, 2012;Sanacora, 2008;Sawada et al, 2005;Silberman et al, 2009;Wallace et al, 2007). Thus, the new knowledge generated by the current study has mechanistic relevance and also provides the rationale for targeting this pathway to develop potential novel therapeutics approaches in the treatment of MDD.…”

Section: Discussionmentioning

confidence: 97%

Evidence Revealing Deregulation of The KLF11-Mao A Pathway in Association with Chronic Stress and Depressive Disorders

Harris¹,

Johnson²,

Duncan

et al. 2014

Neuropsychopharmacol

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The biochemical pathways underlying major depressive disorder (MDD) and chronic stress are not well understood. However, it has been reported that monoamine oxidase A (MAO A, a major neurotransmitter-degrading enzyme) is significantly increased in the brains of human subjects affected with MDD and rats exposed to chronic social defeat (CSD) stress, which is used to model depression. In the current study, we compared the protein levels of a MAO A-transcriptional activator, Kruppel-like factor 11 (KLF11 , also recognized as transforming growth factor-beta-inducible early gene 2) between the brains of 18 human subjects with MDD and 18 control subjects. We found that, indeed, the expression of KLF11 is increased by 36% (po0.02) in the postmortem prefrontal cortex of human subjects with MDD compared with controls. We also observed a positive correlation between KLF11 levels and those of its target gene, MAO A, both in association with MDD. KLF11 protein expression was also increased by 44% (po0.02) in the frontal cortex of KLF11 wild-type mice (Klf11 þ / þ ) vs Klf11 À / À when both exposed to CSD stress. In contrast, locomotor activities, central box duration and sucrose preference were significantly reduced in the stressed Klf11 þ / þ mice, suggesting that Klf11 þ / þ mice are more severely affected by the stress model compared with Klf11 À / À mice. These results serve to assign an important role of KLF11 in upregulating MAO A in MDD and chronic social stress, suggesting that inhibition of the pathways regulated by this transcription factor may aid in the therapeutics of neuropsychiatric illnesses. Thus, the new knowledge derived from the current study extends our understanding of transcriptional mechanisms that are operational in the pathophysiology of common human diseases and thus bears significant biomedical relevance.

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Section: Discussionmentioning

confidence: 97%

Evidence Revealing Deregulation of The KLF11-Mao A Pathway in Association with Chronic Stress and Depressive Disorders

Harris¹,

Johnson²,

Duncan

et al. 2014

Neuropsychopharmacol

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show abstract

“…The MAO A-repressor, R1, in depressive disorder S Johnson et al MAO A synthesis associated with current treatment resistance; (2) prevent the recurrence of depressive episodes because commonly prescribed drugs (such as SSRIs) neither inhibit MAO A levels nor specifically target R1 (Meyer et al, 2009); (3) reduce MAO A-mediated apoptotic cell death, increase neuroprotection, and promote neuroplasticity; maximizing these effects is also relevant to the treatment of depressive disorders (Dwivedi et al, 2006;Sanacora, 2008). Subsequent studies should also address the application of R1 levels as a potential diagnostic marker for depressive disorders and treatment assessment by measuring blood levels of this protein in current and future patients.…”

Section: Discussionmentioning

confidence: 99%

The Reduction of R1, a Novel Repressor Protein for Monoamine Oxidase A, in Major Depressive Disorder

Johnson

Stockmeier

Meyer

et al. 2011

Neuropsychopharmacol

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The novel transcriptional repressor protein, R1 (JPO2/CDCA7L/RAM2), inhibits monoamine oxidase A (MAO A) gene expression and influences cell proliferation and survival. MAO A is implicated in several neuropsychiatric illnesses and highly elevated in major depressive disorder (MDD); however, whether R1 is involved in these disorders is unknown. This study evaluates the role of R1 in depressed subjects either untreated or treated with antidepressant drugs. R1 protein levels were determined in the postmortem prefrontal cortex of 18 untreated MDD subjects and 12 medicated MDD subjects compared with 18 matched psychiatrically normal control subjects. Western blot analysis showed that R1 was significantly decreased by 37.5% (po0.005) in untreated MDD subjects. The R1 level in medicated MDD subjects was also significantly lower (by 30%; po0.05) compared with control subjects, but was not significantly different compared with untreated MDD subjects. Interestingly, the reduction in R1 was significantly correlated with an increase (approximately 40%; po0.05) in MAO A protein levels within the MDD groups compared with controls. Consistent with the change in MAO A protein expression, the MAO A catalytic activity was significantly greater in both MDD groups compared with controls. These results suggest that reduced R1 may lead to elevated MAO A levels in untreated and treated MDD subjects; moreover, the reduction of R1 has been implicated in apoptotic cell death and apoptosis has also been observed in the brains of MDD subjects. Therefore, modulation of R1 levels may provide a new therapeutic target in the development of more effective strategies to treat MDD.

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“…Both Epac1 and Epac2 are expressed in the retina [19]. It has been shown that Epacs have a profound role in cognition, loss of Epacs leads to impairment in memory retrieval in a fear conditioning paradigm [34], and it is also noted that in depressed patients, the Epac2 expression but not Epac1 is altered in the cortex [35]. Besides, Epac2 participates in synaptic plasticity [17,36].…”

Section: Epac2mentioning

confidence: 99%

Epac2-deficiency leads to more severe retinal swelling, glial reactivity and oxidative stress in transient middle cerebral artery occlusion induced ischemic retinopathy

Liu

Yeung

Cheng

et al. 2015

Sci. China Life Sci.

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Ischemia occurs in diabetic retinopathy with neuronal loss, edema, glial cell reactivity and oxidative stress. Epacs, consisting of Epac1 and Epac2, are cAMP mediators playing important roles in maintenance of endothelial barrier and neuronal functions. To investigate the roles of Epacs in the pathogenesis of ischemic retinopathy, transient middle cerebral artery occlusion (tMCAO) was performed on Epac1-deficient (Epac1  ) mice, Epac2-deficient (Epac2  ) mice, and their wild type counterparts (Epac1 +/+ and Epac2). Two-hour occlusion and 22-hour reperfusion were conducted to induce ischemia/reperfusion injury to the retina. After tMCAO, the contralateral retinae displayed similar morphology between different genotypes. Neuronal loss, retinal edema and increase in immunoreactivity for aquaporin 4 (AQP4), glial fibrillary acidic protein (GFAP), peroxiredoxin 6 (Prx6) were observed in ipsilateral retinae. Epac2  ipsilateral retinae showed more neuronal loss in retinal ganglion cell layer, increased retinal thickness and stronger immunostaining of AQP4, GFAP, and Prx6 than those of Epac2 However, Epac1 ipsilateral retinae displayed similar pathology as those in Epac1 +/+ mice. Our observations suggest that Epac2-deficiency led to more severe ischemic retinopathy after retinal ischemia/reperfusion injury. Epac, retina, ischemia, retinopathyCitation: Liu J, Yeung PKK, Cheng L, Lo ACY, Chung SSM, Chung SK. Epac2-deficiency leads to more severe retinal swelling, glial reactivity and oxidative stress in transient middle cerebral artery occlusion induced ischemic retinopathy.

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Differential and Brain Region–Specific Regulation of Rap-1 and Epac in Depressed Suicide Victims

Abstract: Given the importance of Rap-1 in neuroprotection and synaptic plasticity, our findings of differential regulation of Rap-1 and Epac between brain regions suggest the relevance of these molecules in the pathophysiology of depression.

Cited by 44 publications

References 64 publications

Evidence Revealing Deregulation of The KLF11-Mao A Pathway in Association with Chronic Stress and Depressive Disorders

Evidence Revealing Deregulation of The KLF11-Mao A Pathway in Association with Chronic Stress and Depressive Disorders

The Reduction of R1, a Novel Repressor Protein for Monoamine Oxidase A, in Major Depressive Disorder

Epac2-deficiency leads to more severe retinal swelling, glial reactivity and oxidative stress in transient middle cerebral artery occlusion induced ischemic retinopathy

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