Elsevier

European Journal of Pharmacology

Volume 788, 5 October 2016, Pages 255-260
European Journal of Pharmacology

Review
Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca2+/cAMP intracellular signalling interaction

https://doi.org/10.1016/j.ejphar.2016.06.034Get rights and content

Abstract

In 2013, we discovered that the entitled “calcium paradox” phenomenon, which means a paradoxical sympathetic hyperactivity produced by l-type Ca2+ channel blockers (CCBs), used in antihypertensive therapy, is due to interaction between the intracellular signalling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP interaction). In 2015, we proposed that the pharmacological manipulation of this interaction could be a new therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. Besides the paradoxical sympathetic hyperactivity produced by CCBs, several clinical studies have been demonstrating pleiotropic effects of CCBs, including neuroprotective effects. CCBs genuinely exhibit cognitive-enhancing abilities and reduce the risk of dementia, including Alzheimer’s, Parkinson´s disease and others. The molecular mechanisms involved in these pleiotropic effects remain under debate. Our recent discovery that the “calcium paradox” phenomenon is due to Ca2+/cAMP interaction may provide new insights for the pharmacological treatment of neurological and psychiatric disorders, including enhancement of current therapies mainly by reducing adverse effects, and improving effectiveness of modern medicines. Whether Ca2+/cAMP interaction is involved in CCBs pleiotropic effects also deserves special attention. Then, the pharmacological manipulation of the Ca2+/cAMP interaction could be a more efficient therapeutic strategy for increasing neurotransmission in psychiatric disorders, and producing neuroprotection in the neurodegenerative diseases. Thus, in this review we summarize the current knowledge of this field, making new directions and future perspectives.

Introduction

Neurological and psychiatric disorders have been considered severe global illness, becoming more and more common each decade (Zamponi, 2016). Because of their devastating symptoms, they have been considered as a leading cause of disability all over the world (De-Paula et al., 2012, Kaster et al., 2016, Köhler et al., 2016, Mohamed et al., 2016, Salat et al., 2016, Zamponi, 2016). Neurological disorders which result from neurodegeneration (neurodegenerative diseases) commonly begin years before a clinical diagnosis can be consistently made (asymptomatic/slightly symptomatic patients), for example Alzheimer´s and Parkinson´s diseases (De-Paula et al., 2012, Salat et al., 2016). The early diagnostic phase of these diseases offer an opportunity for therapies, for example: those aimed to interrupt or preventing the progression of these diseases, and their many complications side effects, could be more beneficial. However, no such efficient therapies are available at the present moment (Mohamed et al., 2016, Salat et al., 2016). Thus, revealing the mechanisms of neurodegeneration from the earliest stages could lead to the development of new interventions, whose therapeutic potential will need to be assessed in adequately designed clinical trials (De-Paula et al., 2012, Hayes et al., 2010, Salat et al., 2016). Advances in the understanding of this early phase of neurodegenerative diseases will lead to the identification of biomarkers of neurodegeneration and its progression. These biomarkers will help to identify the ideal population to be included, and the most appropriate outcomes to be assessed in clinical trials of medicines. Thus, in this review we discuss novel strategies to treat neurological and psychiatric disorders, throughout our recent discovery entitled “calcium paradox” phenomenon due to Ca2+/cAMP interaction (Bergantin et al., 2013, Bergantin et al., 2015, Caricati-Neto et al., 2015).

Section snippets

Current therapies to treat neurological and psychiatric disorders

Here we discuss current therapies to treat neurological and psychiatric disorders, including Alzheimer´s and Parkinson´s diseases, and depression.

Implications of the Ca2+/cAMP interaction: a brief review

Numerous experiments initiated sixty years ago using catecholaminergic cells originated the concept of stimulus-secretion coupling to elucidate neurotransmitter release and hormone secretion. This concept was initially resulted from the study of cat adrenal gland perfused with acetylcholine executed by Douglas and Rubin in the 1960s (Douglas and Rubin, 1961). The discovery that increase in the cytosolic Ca2+ concentration ([Ca2+]c) was a basic requirement for exocytosis in adrenal

Conclusions and future directions

The diagnosis of neurological and psychiatric disorders, especially neurodegenerative diseases like Parkinson´s and Alzheimer´s diseases relies critically on clinical diagnosis of patients. In addition, emerging therapies may supplement clinical assessment in the next years. Although pharmacological therapies have been largely unsuccessful in attenuating neurodegenerative diseases symptoms, targeting potential risk factors aiming to decrease incidence of these neurodegenerative diseases is an

Disclosure statement

Bergantin and Caricati-Neto thank the continued financial support from CAPES, CNPq and FAPESP (Bergantin´s Postdoctoral Fellowship FAPESP #2014/10274–3).

Conflict of interest statement

None.

Authorship contribution statement

Bergantin and Caricati-Neto wrote this review, and approved the final version.

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