ReviewChallenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca2+/cAMP intracellular signalling interaction
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.
References (31)
Interactions between intracellular free Ca2+ and cyclic AMP in neuroendocrine cells
Cell Calcium
(2012)- et al.
Novel model for “calcium paradox” in sympathetic transmission of smooth muscles: role of cyclic AMP pathway
Cell Calcium
(2013) - et al.
Cognitive benefits of memantine in Alzheimer’s 5XFAD model mice decline during advanced disease stages
Pharmacol. Biochem. Behav.
(2016) - et al.
Novel approaches for the management of depressive disorders
Eur. J. Pharmacol.
(2016) - et al.
Multi-target novel neuroprotective compound ITH33/IQM9.21 inhibits calcium entry, calcium signals and exocytosis
Cell Calcium
(2011) - et al.
Amyloid cascade in Alzheimer’s disease: Recent advances in medicinal chemistry
Eur. J. Med. Chem.
(2016) - et al.
Verapamil enhances the non-adrenergic twitch response of rat vas deferens
Eur. J. Pharmacol.
(1987) - et al.
Age-related working memory impairment is correlated with increases in the l-type calcium channel protein α1D (Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment
Brain Res. Mol. Brain Res.
(2003) - et al.
Linking structure to function: recent lessons from inositol 1,4,5-trisphosphate receptor mutagenesis
Cell Calcium
(2010) - et al.
Calcium-dependent exocytosis in bovine adrenal medullary cells with leaky plasma membranes
Nature
(1978)
A calcium paradox in the context of neurotransmission
J. Pharm. Pharmacol.
Pharmacological implications of the Ca2+/cAMP signalling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders
Pharmacol. Res. Perspect.
‘Rejuvenation’ protects neurons in mouse models of Parkinson's disease
Nature
Adenosine receptors activate adenylate cyclase and enhance secretion from bovine adrenal chromaffin cells in the presence of forskolin
J. Neurochem.
Adenylyl cyclases and the interaction between calcium and cAMP signalling
Nature
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2019, Pharmacological ResearchCitation Excerpt :Furthermore, Ca2+ channels in the cytoplasm, and in intracellular organelles, help to maintain the intracellular Ca2+ homeostasis [8]. In addition to these issues, modulators of the glutamatergic system, such as ketamine, also have turned into the vanguard for the therapies to combat depression, especially for depression which demonstrates to be resistant against conventional treatment, including suicidal ideation [7,8]. Nevertheless, the theory of monoamine of depression is still the frontline for the field in the clinical trials, which assumes that a disbalance in the neurotransmission of monoamines is intimately associated to the clinical symptoms of the disease [7,8].