From a "Eureka Insight" to a Novel Potential Therapeutic Target to Treat Alzheimer's Disease

Abstract

It has been almost 4 years since we revealed the solution for the enigma of the so-called "calcium paradox". Our discovery of the involvement of Ca²⁺/cAMP signaling interaction in the regulation of neurotransmitter release, and neuro protection, was clearly a serendipitous discovery. It has produced new avenues in the understanding of the cellular and molecular mechanisms involved in the pathogenesis of neurological and psychiatric disorders, such as Alzheimer's disease. Interestingly, this discovery initiated decades ago when numerous clinical studies have reported that use of L-type Ca²⁺ channel blockers (CCBs) by hypertensive patients decreased arterial pressure, but produced typical symptoms of sympathetic hyperactivity, such as tachycardia and increment of catecholamine plasma levels. Despite these adverse effects of CCBs have been initially attributed to adjust reflex of arterial pressure, during almost four decades this enigmatic phenomenon (the so-called "calcium paradox") remained unclear. In 2013, through an ingenious experiment, we discovered that this phenomenon was resulting of increment of transmitter release from sympathetic neurons, and adrenal chromaffin cells, stimulated by CCBs due to its interference on the Ca²⁺/cAMP signaling interaction. In this way, our discovery of the role of Ca²⁺/cAMP signaling interaction in the neurotransmitter release, and neuronal death triggered by cytosolic Ca²⁺ overload, opened novel adventures for the development of new pharmacological strategies more effective for the treatment of neurological and psychiatric disorders resulting of neurotransmitter release deficit, and neuronal death. These novel concepts have been extensively documented in several cited international papers of our own authorship (Bergantin and Caricati-Neto), and in an international book.

Keywords

Ca²⁺/cAMP signaling interaction, Calcium paradox, Neurological/psychiatric disorders

Introduction

Classically, the notion of stimulus-secretion coupling to explain neurotransmitters and hormones release has been resulted from ingenious experiments performed by Douglas and Rubin in the 1960s [1]. Complementing their concepts, Baker and Knight revealed in 1970's that a rise in the cytosolic Ca²⁺ concentration ([Ca²⁺]_c) is an elementary requirement to trigger transmitter release [2]. Indeed, the definite demonstration of a direct relationship between neurotransmitter release and rise in [Ca²⁺]_c derived from the fundamental experiments performed by the Nobel laureate Erwin Neher [3]. More recently, many results have shown that cAMP increases neurotransmitter release at many synapses in autonomic nervous system of vertebrate, including sympathetic neurons [4]. Although the cellular mechanisms involved in these enhancer effects of cAMP on the release of neurotransmitters and hormones are under debate, the evidences indicate that this important intracellular messenger modulates signaling pathways mediated by Ca²⁺ involved in the regulation of neurotransmitter, and hormones release.

The Ca²⁺/Camp Signaling Interaction as a Universally-Operated Concept

The interaction between the intracellular signaling pathways mediated by Ca²⁺ and cAMP, named Ca²⁺/cAMP signaling interaction, has been widely studied in different cell types and tissues. This nowadays accepted concept assumes that this interaction results in synergistic actions of these intracellular messengers on cell functions regulated by adenylyl cyclases (ACs), or phosphodiesterases (PDEs) [5-8]. The Ca²⁺/cAMP signaling interaction has particularly been extensively studied at the endoplasmic reticulum (ER) Ca²⁺ channels, such as Ca²⁺ channels regulated by ryanodine receptors (RyR) [5-8]. Our own experiments established that Ca²⁺/cAMP signaling interaction plays a key role in the regulation of neurotransmitter release from neurons and neuroendocrine cells [5-8]. Then, dysfunctions of cellular homeostasis of Ca²⁺ and/or cAMP in these cells could result in the dysregulation of Ca²⁺/cAMP signaling interaction, and could be a novel therapeutic goal for medicines.

From a "Eureka Insight" to a Novel Potential Therapeutic Target to Treat Alzheimer's Disease

Indeed, several medical studies have been evidencing that acute and chronic use of L-type Ca²⁺ channel blockers (CCBs) in the antihypertensive therapy, such as nifedipine and verapamil, decreased peripheral vascular resistance and arterial pressure arterial, but produced typical symptoms of sympathetic hyperactivity such as tachycardia, and increment of catecholamine plasma levels [9]. Despite these adverse effects of CCBs have been initially attributed to adjust reflex of arterial pressure, during almost four decades the cellular and molecular mechanisms involved this enigmatic phenomenon named "calcium paradox" remained without additional explanation.

In 2013, through an ingenious experiment, we discovered that the "calcium paradox" phenomenon was resulting of increment of transmitter release from sympathetic neurons, and adrenal chromaffin cells, stimulated by CCBs due to its interference on the Ca²⁺/cAMP signaling interaction. Using isolated tissues richly innervated by sympathetic nerves (rat vas deferens) to exclude the influence of adjusting reflex, we showed that neurogenic responses of the vas deferens were completely inhibited by L-type CCBs in high concentrations (> 1 μmol/L), but unpredictably, and paradoxically, potentiated in concentrations below 1 μmol/L, characterized by sympathetic hyperactivity induced by CCBs [10-12]. Our studies showed that this paradoxical sympathetic hyperactivity is caused by increment of neurotransmitter release from sympathetic neurons produced by L-type CCBs due to its interference on the Ca²⁺/cAMP signaling interaction [5-8] (Figure 1).

Neurotransmitter release stimulation, and reduction of neuronal death triggered by cytosolic Ca²⁺ overload, can be achieved due to pharmacological regulation of the Ca²⁺/cAMP signaling interaction. The reduction of Ca²⁺ influx through L-type voltage-activated Ca²⁺channels produced by CCBs enhances the adenylyl cyclase activity (and consequently cAMP). These CCBs-effects can be potentiated by cAMP-enhancer compounds (like PDEs inhibitors). PDEs-Phosphodiesterases, RyR-Ryanodine receptors, IP₃R-IP₃ receptors, SERCA-Sarcoendoplasmic reticulum Ca²⁺-ATPase.

In addition, several studies have showed that increase of cytosolic cAMP concentration ([cAMP]c) stimulates neuroprotective response [13,14]. In this way, increase of [cAMP]_c by interfering in the Ca²⁺/cAMP signaling interaction could attenuate neuronal death triggered by cytosolic Ca²⁺ overload [5-8]. Then, the pharmacological handling of the Ca²⁺/cAMP signaling interaction produced by combination of the L-type CCBs used in the antihypertensive therapy, and [cAMP]_c enhancer compounds used in the anti-depressive therapy such as rolipram, could be a new pharmacological strategy for enhancing neurotransmission in neurological and psychiatric disorders resulting of neurotransmitter release deficit, and/or neuronal death [5-8]. These findings could open a new avenue for the drug development more effective and safer for the treatment of Alzheimer's diseases [15-18].

In fact, it was demonstrated that the prescription of L-type CCBs reduces motor symptoms, and reduces progressive neuronal death in animal model of Parkinson's disease, indicating that L-type CCBs are potentially viable neuroprotective pharmaceuticals [19]. Intriguingly, a 1-decade study involving thousands senile hypertensive patients demonstrated that prescription of L-type CCBs reduced blood pressure, and risk of dementia, in hypertensive patients, indicating that these pharmaceuticals could be clinically used to treat neurodegenerative diseases [20]. These results for the neuroprotective effects of CCBs have been reinvestigated in thousands elderly hypertensive patients with memory dysfunction [21]. These studies concluded that patients who have taken CCBs had their risk of cognitive dysfunction decreased, such as Alzheimer's disease [21]. These findings reinforce the idea that reduction of cytosolic Ca²⁺ overload produced by L-type CCBs due to blockade of Ca²⁺ influx could be an alternative pharmacological goal to reduce, or prevent, neuronal death in neurodegenerative diseases.

Conclusion

From a "eureka insight" to a novel potential therapeutic target to treat Alzheimer's disease. Pharmacological handling of the Ca²⁺/cAMP signaling interaction could be a more efficient and safer therapeutic strategy for stimulating neurotransmission compromised by neurotransmitter release deficit, and attenuating neuronal death.

Disclosure Statement

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

The authors also thank Elsevier-"author use": Reuse of portions or extracts from the article in other works : https://www.elsevier.com/__data/assets/pdf_file/0007/55654/AuthorUserRights.pdf.

References

1. Douglas WW, Rubin RP (1961) The role of calcium in the secretory response of the adrenal medulla to acetylcholine. J Physiol 159: 40-57.
2. Baker PF, Knight DE (1978) Calcium-dependent exocytosis in bovine adrenal medullary cells with leaky plasma membranes. Nature 276: 620-622.
3. Neher E, Zucker RS (1993) Multiple calcium-dependent processes related to secretion in bovine chromaffin cells. Neuron 10: 21-30.
4. Chern YJ, Kim KT, Slakey LL, et al. (1988) Adenosine receptors activate adenylate cyclase and enhance secretion from bovine adrenal chromaffin cells in the presence of forskolin. J Neurochem 50: 1484-1493.
5. Caricati-Neto A, García AG, Bergantin LB (2015) Pharmacological implications of the Ca²⁺/cAMP signalling interaction: from risk for antihypertensive therapy to potential beneficial for neurological and psychiatric disorders. Pharmacol Res Perspect 3.
6. Bergantin LB, Souza CF, Ferreira RM, et al. (2013) Novel model for "calcium paradox" in sympathetic transmission of smooth muscles: role of cyclic AMP pathway. Cell Calcium 54: 202-212.
7. Bergantin LB, Jurkiewicz A, García AG, et al. (2015) A Calcium Paradox in the Context of Neurotransmission. Journal of Pharmacy and Pharmacology 3: 253-261.
8. Bergantin LB, Caricati-Neto A (2016) Challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca²⁺/cAMP intracellular signalling interaction. Eur J Pharmacol 788: 255-260.
9. Grossman E, Messerli FH (1998) Effect of calcium antagonists on sympathetic activity. Eur Heart J 19: 27-31.
10. Kreye VA, Luth JB (1975) Proceedings: verapamil-induced phasic contractions of the isolated rat vas deferens. Naunyn Schmiedebergs Arch Pharmacol 287: 43.
11. French AM, Scott NC (1981) A comparison of the effects of nifedipine and verapamil on rat vas deferens. Br J Pharmacol 73: 321-323.
12. Moritoki H, Iwamoto T, Kanaya J, et al. (1987) Verapamil enhances the non-adrenergic twitch response of rat vas deferens. Eur J Pharmacol 140: 75-83.
13. Sommer N, Loschmann PA, Northoff GH, et al. (1995) The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med 1: 244-248.
14. Xiao L, O'Callaghan JP, O'Donnell JM (2011) Effects of repeated treatment with phosphodiesterase-4 inhibitors on cAMP signaling, hippocampal cell proliferation, and behavior in the forced-swim test. J Pharmacol Exp Ther 338: 641-647.
15. Bergantin LB, Caricati-Neto A (2016) Insight from "Calcium Paradox" due to Ca²⁺/cAMP Interaction: Novel Pharmacological Strategies for the Treatment of Depression. Int Arch Clin Pharmacol 2: 1-4.
16. Bergantin LB, Caricati-Neto A (2016) Novel Insights for Therapy of Parkinson's disease: Pharmacological Modulation of the Ca²⁺/cAMP Signalling Interaction. Austin Neurol & Neurosci 1: 1009.
17. Bergantin LB, Caricati-Neto A (2016) Recent advances in pharmacotherapy of neurological and psychiatric disorders promoted by discovery of the role of Ca²⁺/cAMP signaling interaction in the neurotransmission and neuroprotection. Adv Pharmac J 1: 66-70.
18. Bergantin LB, Caricati-Neto A (2016) From discovering "calcium paradox" to Ca²⁺/cAMP interaction: Impact in human health and disease. Global Congress on Tissue Engineering, Regenerative & Precision Medicine, USA.
19. Ilijic E, Guzman JN, Surmeier DJ (2011) The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. Neurobiol Dis 43: 364-371.
20. Wu CL, Wen SH (2016) A 10-year follow-up study of the association between calcium channel blocker use and the risk of dementia in elderly hypertensive patients. Medicine 95: e4593.
21. Hanon O, Pequignot R, Seux ML, et al. (2006) Relationship between antihypertensive drug therapy and cognitive function in elderly hypertensive patients with memory complaints. J Hypertens 24: 2101-2107.