Inhibitor of Phosphodiestearse-4 improves memory deficits, oxidative stress, neuroinflammation and neuropathological alterations in mouse models of dementia of Alzheimer’s Type

Kumar, Amit; Singh, Nirmal

doi:10.1016/j.biopha.2017.01.059

Cited by 54 publications

(30 citation statements)

References 58 publications

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“…Targeting NO-cGMP-PKG-ERK signaling pathway may represent an interesting approach for the development of new drugs in the treatment of memory dysfunctions occurring in neurodegenerative and psychiatric diseases, among others Alzheimer’s disease and dementia. Initial promising findings in this direction have been reported regarding the use of PDE inhibitors ( Kumar and Singh, 2017 ; Prickaerts et al, 2017 ) or sGC stimulator ( Montfort et al, 2017 ) in the treatment of neuroinflammatory and neuropathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders

et al. 2018

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Mounting evidence suggests that the guanine-based purines stand out as key player in cell metabolism and in several models of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases. Guanosine (GUO) and guanine (GUA) are extracellular signaling molecules derived from the breakdown of the correspondent nucleotide, GTP, and their intracellular and extracellular levels are regulated by the fine-tuned activity of two major enzymes, purine nucleoside phosphorylase (PNP) and guanine deaminase (GDA). Noteworthy, GUO and GUA, seem to play opposite roles in the modulation of cognitive functions, such as learning and memory. Indeed GUO, despite exerting neuroprotective, anti-apoptotic and neurotrophic effects, causes a decay of cognitive activities, whereas GUA administration in rats results in working memory improvement (prevented by L-NAME pre-treatment). This study was designed to investigate, in a model of SH-SY5Y neuroblastoma cell line, the signal transduction pathway activated by extracellular GUA. Altogether, our results showed that: (i) in addition to an enhanced phosphorylation of ASK1, p38 and JNK, likely linked to a non-massive and transient ROS production, the PKB/NO/sGC/cGMP/PKG/ERK cascade seems to be the main signaling pathway elicited by extracellular GUA; (ii) the activation of this pathway occurs in a pertussis-toxin sensitive manner, thus suggesting the involvement of a putative G protein coupled receptor; (iii) the GUA-induced NO production, strongly reduced by cell pre-treatment with L-NAME, is negatively modulated by the EPAC-cAMP-CaMKII pathway, which causes the over-expression of GDA that, in turn, reduces the levels of GUA. These molecular mechanisms activated by GUA may be useful to support our previous observation showing that GUA improves learning and memory functions through the stimulation of NO signaling pathway, and underscore the therapeutic potential of oral administration of guanine for treating memory-related disorders.

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Section: Discussionmentioning

confidence: 99%

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders

et al. 2018

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“…A drug containing the PDE1 inhibitor vinpocetine improved memory function in elderly subjects [66], as have 2 novel PDE4 inhibitors from Dart Neuroscience and Tetra Discovery Partners (see [55]). In animal models, pharmacological inhibition or genetic deletion of PDE2 [67], PDE3 [68], PDE4 [69–72], and PDE8B [73] have all provided protection against some type of age-related cognitive decline. These studies suggest that increasing cAMP signaling in a brain region-specific manner may prove a viable mechanism for treating age-related decline in brain function.…”

Section: Alterations In Cyclic Nucleotide Signaling Associated Witmentioning

confidence: 99%

Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain

Kelly

2018

Cellular Signalling

127

118

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Deficits in brain function that are associated with aging and age-related diseases benefit very little from currently available therapies, suggesting a better understanding of the underlying molecular mechanisms is needed to develop improved drugs. Here, we review the literature to test the hypothesis that a break down in cyclic nucleotide signaling at the level of synthesis, execution, and/or degradation may contribute to these deficits. A number of findings have been reported in both the human and animal model literature that point to brain region-specific changes in Galphas (a.k.a. Gαs or Gsα), adenylyl cyclase, 3',5'-adenosine monophosphate (cAMP) levels, protein kinase A (PKA), cAMP response element binding protein (CREB), exchange protein activated by cAMP (Epac), hyperpolarization-activated cyclic nucleotide-gated ion channels (HCNs), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), soluble and particulate guanylyl cyclase, 3',5'-guanosine monophosphate (cGMP), protein kinase G (PKG) and phosphodiesterases (PDEs). Among the most reproducible findings are 1) elevated circulating ANP and BNP levels being associated with cognitive dysfunction or dementia independent of cardiovascular effects, 2) reduced basal and/or NMDA-stimulated cGMP levels in brain with aging or Alzheimer's disease (AD), 3) reduced adenylyl cyclase activity in hippocampus and specific cortical regions with aging or AD, 4) reduced expression/activity of PKA in temporal cortex and hippocampus with AD, 5) reduced phosphorylation of CREB in hippocampus with aging or AD, 6) reduced expression/activity of the PDE4 family in brain with aging, 7) reduced expression of PDE10A in the striatum with Huntington's disease (HD) or Parkinson's disease, and 8) beneficial effects of select PDE inhibitors, particularly PDE10 inhibitors in HD models and PDE4 and PDE5 inhibitors in aging and AD models. Although these findings generally point to a reduction in cyclic nucleotide signaling being associated with aging and age-related diseases, there are exceptions. In particular, there is evidence for increased cAMP signaling specifically in aged prefrontal cortex, AD cerebral vessels, and PD hippocampus. Thus, if cyclic nucleotide signaling is going to be targeted effectively for therapeutic gain, it will have to be manipulated in a brain region-specific manner.

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“…Based on this finding, application of synthetic analogs of cyclic AMP, activators of adenylyl cyclase, or inhibitors of PDE might suppress the pro-inflammatory phenotype of microglial cells via elevation of cyclic AMP. Notably, PDE inhibitors, such as rolipram for PDE4, sildenafil and yonkenafil for PDE5 (Zhao et al, 2016), and non-selective PDE inhibitors (e.g., ibudilast), have been proposed as potential therapeutic drugs for neurodegenerative disorders, including MS (Pifarre et al, 2011), AD (Myeku et al, 2016; Kumar and Singh, 2017; Rabal et al, 2018; Xu et al, 2018), and PD (Kinoshita et al, 2017; Schwenkgrub et al, 2017).…”

Section: Potentials Of Microglia As a Therapeutic Target For Pdmentioning

confidence: 99%

Pharmacological Targeting of Microglial Activation: New Therapeutic Approach

Liu

Wang

Liu

et al. 2019

Front. Cell. Neurosci.

109

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Mounting evidence suggests that neuroinflammation is not just a consequence but a vital contributor to the development and progression of Parkinson’s disease (PD). Microglia in particular, may contribute to the induction and modulation of inflammation in PD. Upon stimulation, microglia convert into activated phenotypes, which exist along a dynamic continuum and bear different immune properties depending on the disease stage and severity. Activated microglia release various factors involved in neuroinflammation, such as cytokines, chemokines, growth factors, reactive oxygen species (ROS), reactive nitrogen species (RNS), and prostaglandins (PGs). Further, activated microglia interact with other cell types (e.g., neurons, astrocytes and mast cells) and are closely associated with α-synuclein (α-syn) pathophysiology and iron homeostasis disturbance. Taken together, microglial activation and microglia-mediated inflammatory responses play essential roles in the pathogenesis of PD and elucidation of the complexity and imbalance of microglial activation may shed light on novel therapeutic approaches for PD.

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Inhibitor of Phosphodiestearse-4 improves memory deficits, oxidative stress, neuroinflammation and neuropathological alterations in mouse models of dementia of Alzheimer’s Type

Cited by 54 publications

References 58 publications

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders

Uncovering the Signaling Pathway behind Extracellular Guanine-Induced Activation of NO System: New Perspectives in Memory-Related Disorders

Cyclic nucleotide signaling changes associated with normal aging and age-related diseases of the brain

Pharmacological Targeting of Microglial Activation: New Therapeutic Approach

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