Role of Cortisol and Dehydroepiandrosterone on RACK1/PKC Signalling and Consequences in Immunosenescence

Over the past 15 years, it was demonstrated that defective protein kinase C (PKC) signal transduction machinery correlates to the decline of immune functions associated with aging. Experimental evidence suggest that altered PKC signalling results in impaired response to lipopolisaccaride (LPS) stimulation and cytokine release. Such defective signalling is due to reduced expression of receptor for activated C kinase 1 (RACK1) and to age-related alteration of the hormonal balance between cortisol and dehydroepiandrosterone (DHEA): cortisol levels remain substantially unchanged while DHEA levels decline with aging. These aspects are particularly relevant for the functional PKC signalling system because DHEA administration in vivo and in vitro in aged animals and in human cells can reestablish the levels of RACK1 and thus the function of the PKC signalling cascade. There is also evidence that cortisol and DHEA have opposite effect on the transcriptional regulation of the gene encoding for RACK1 and known as GNB2L1. At transcriptional level, cortisol has a peculiar function of a negative regulator of the RACK1 promoter, while the effect of DHEA seems to derive from a complex influence on the functions and post-transcriptional regulation of the glucocorticoid receptor (GR). Here we discuss the role of PKC/RACK1 signalling in the context of immune cells and immunosenescence also focusing on the role of cortisol and DHEA in the regulation of RACK1 expression

PDE4 as a target for cognition enhancement

INTRODUCTION: The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs. AREAS COVERED: PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation. EXPERT OPINION: PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors