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Citation: Bergantin LB and Caricati-Neto A. Novel Insights for Therapy of Parkinson’s disease: Pharmacological
Modulation of the Ca2+/cAMP Signalling Interaction. Austin Neurol & Neurosci. 2016; 1(2): 1009.
Austin Neurol & Neurosci - Volume 1 Issue 2 - 2016
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Bergantin et al. © All rights are reserved
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Abstract
Our discovery of the “calcium paradox” phenomenon due to interaction
between Ca2+/cAMP intracellular signalling pathways involved in
catecholaminergic transmission may provide new insights for the treatment
of psychiatric disorders, such as Parkinson’s disease. This disease is mainly
resulting by reduction of dopamine release in striatal dopaminergic neurons. In
addition, since 1975 several clinical studies have reported that administration
of L-type Ca2+ Channel Blockers (CCBs) in hypertensives produces reduction
in vascular resistance and arterial pressure, associated with an increase in
plasma noradrenaline levels and tachycardia characterized by sympathetic
hyperactivity. Despite these adverse effects of CCBs have been initially
attributed to adjust reex of arterial pressure, during almost four decades these
enigmatic phenomena remained unclear. In 2013, we discovered that this
paradoxical sympathetic hyperactivity produced by CCBs is due to interaction
of the Ca2+/cAMP intracellular signalling pathways. Also, clinical studies have
been reporting neuroprotective effects of CCBs in neurodegenerative disorders,
including for Parkinson’s disease. The molecular mechanisms involved in
these pleiotropic effects remain under debate. Then, the pharmacological
manipulation of the Ca2+/cAMP interaction could be a more efcient therapeutic
strategy for increasing neuroprotection and dopamine neurotransmitter release
in Parkinson’s disease.
Keywords: Parkinson’s disease; Ca2+/cAMP interaction
Current Therapy to Treat Parkinson’s
Disease
Dopamine loss in the substantia nigra, which results from
reduction of dopamine release in striatal dopaminergic neurons
due to neuronal death, outcomes in the recognizable core signs of
asymmetrical bradykinesia and hypokinesia (slowness and reduced
amplitude of movement), muscle rigidity (stiness) and rest
tremor, consequences from modifying motor control. Rest tremor,
prominent asymmetry and a good response to levodopa are the
features that most accurately predict Parkinson’s disease pathology
[5]. e tremor-dominant form of Parkinson’s disease tends to run
a more benign course than typical Parkinson’s disease. Early falls
or autonomic symptoms, and a response to Parkinson’s disease
medicines should raise evidences about the diagnosis [5]. Medication-
induced Parkinsonism due to commonly prescribed dopamine-
blocking medications, such as antipsychotics (eg: haloperidol,
risperidone) and antiemetics (eg: metoclopramide, prochlorperazine)
should be excluded in Parkinson’s patients. Functional imaging of
the dopaminergic system using cerebral single photon emission
computed tomography or positron emission tomography can be
useful in diagnosis of early Parkinson’s disease [1,5]. Positron emission
tomography studies examining the rate of decline in dopamine-
producing cells suggest that humans have already lost 50%-70% of
their nigral neurons, before they develop motor symptoms [5], and
it has been estimated that the duration of this “presymptomatic”
Introduction
Parkinson’s disease is a neurodegenerative disease resulting
mainly by reduction of dopamine release from striatal dopaminergic
neurons due to neuronal death [1]. Neurodegeneration in Parkinson’s
disease begins years before a clinical diagnosis can be consistently
made (asymptomatic/slightly symptomatic patients). e early
diagnostic phase of the disease oers an opportunity for therapies,
for example: those aimed to interrupt or preventing the progression
of this disease, and its many complications side eects, could be more
benecial, but no such ecient therapies are available at the present
moment. us, revealing the mechanisms of neurodegeneration from
the earliest stages, however, could lead to the development of new
interventions, whose therapeutic potential will need to be assessed in
adequately designed clinical trials [1]. Advances in the understanding
of this early phase of Parkinson’s disease will lead to the identication
of biomarkers of neurodegeneration and its progression. ese
biomarkers will help to identify the ideal population to be included,
and the most appropriate outcomes to be assessed in clinical trials
of medicines. Potential risks for asymptomatic patients developing
Parkinson’s disease, and individuals who do not wish to know their
mutation status, could pose specic ethical dilemmas in the design
of clinical trials. In this chapter, we discuss novel strategies to treat
Parkinson’s disease, throughout our recent discovery entitled
“calcium paradox” phenomenon due to interaction of Ca2+/cAMP
intracellular signalling pathways [2-4].
Mini Review
Novel Insights for Therapy of Parkinson’s disease:
Pharmacological Modulation of the Ca2+/cAMP Signalling
Interaction
Bergantin LB* and Caricati-Neto A
Department of Pharmacology, Universidade Federal de
Sao Paulo, Escola Paulista de Medicina, Laboratory of
Autonomic and Cardiovascular Pharmacology, Sao Paulo,
Brazil
*Corresponding author: Leandro Bueno Bergantin,
Department of Pharmacology, Universidade Federal de
Sao Paulo, Escola Paulista de Medicina, Laboratory of
Autonomic and Cardiovascular Pharmacology, Sao Paulo,
Brazil
Received: August 26, 2016; Accepted: October 18,
2016; Published: October 21, 2016
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phase is about 5 years. Early diagnosis will become a critical issue if
eective neuroprotective drugs become available. In fact, increasing
dopamine, mainly by Levodopa combined with a dopa-decarboxylase
inhibitor remains the most potent drug therapy for reversing motor
impairment. A higher maintenance dose of Levodopa (eg: 200 mg
three times daily compared with an initial dose of 100 mg three times
daily) provides slightly greater benet for reducing motor symptoms,
but at the cost of earlier wearing-o symptoms and dyskinesias
[5]. e combination of novel concepts may lead to advances in
Parkinson’s disease research with the promise of nding compounds
that are both eective, and fast-acting, including in patients who have
tried other therapies with limited success. In conclusion, new insights
for more ecient pharmacological treatments of Parkinson’s disease
are clearly needed.
Novel Insights for Therapy of Parkinson’s
Disease: Pharmacological Modulation of the
Ca2+/cAMP Signalling Interaction
Discovery of the role of interaction of intracellular
signalling pathways mediated by Ca2+ and cAMP in
neurotransmitter release: 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. is concept was initially resulted from the study of cat
adrenal gland perfused with acetylcholine executed by Douglas and
Rubin in the 1960’s [6]. e discovery that increase in the cytosolic
Ca2+ concentration ([Ca2+]c) was a basic requirement for exocytosis
in adrenal catecholaminergic cells was made by Baker and Knight
in 1970’s [7]. In addition, some studies showed that cAMP rises
transmitter release at several synapses in autonomic nervous system of
vertebrate, including sympathetic neurons [8]. Although the cellular
and molecular mechanisms involved in these synergistic actions of
cAMP on the exocytosis of neurotransmitter and hormones remain
uncertain, the evidences suggest that this intracellular messenger
can participate in ne regulation of exocytosis due to its modulatory
action on the intracellular Ca2+ signals.
In fact, the hypothesis for an interaction between the intracellular
signalling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP
interaction) has been extensively studied in many cells and tissues.
Generally, this interaction results in synergistic eects on cell
functions [2-4] and occurs at the level of Adenylyl Cyclases (ACs) or
Phosphodiesterases (PDEs) (Figure 1). e Ca2+/cAMP interaction
has particularly been extensively studied at the Ca2+ channels
[e.g: Ryanodine Receptors (RyR)] of the Endoplasmic Reticulum
(ER) [2-4]. Phosphorylation of RyR by Protein Kinase A (PKA),
and also Inositol trisphosphate receptor (IP3R) at submaximal IP3
concentrations, may increase the open probability of ER Ca2+ stores,
amplifying Ca2+-Induced Ca2+ Release (CICR) mechanism and
cellular responses [2-4] (Figure 1). en, dysfunctions of cellular
homeostasis of Ca2+ and/or cAMP in these cells could result in the
dysregulation of Ca2+/cAMP interaction and exocytotic response, or
could be a novel therapeutic target for medicines (Figure 1).
Cellular homeostasis of Ca2+ and/or cAMP in these cells could
be a novel therapeutic target for medicines, according to our
previous studies [2-4]. Considering our model in which increment
of [cAMP]c stimulates Ca2+ release from endoplasmic reticulum,
it may be plausible that the therapeutic use of the PDE inhibitor
rolipram in combination with low doses of verapamil to potentiate
neurotransmission in the areas of central nervous system involved
in neurological/psychiatric disorders in which neurotransmission is
reduced, including Parkinson’s disease.
Paradoxical effects of CCBs on neurotransmission and
their pleiotropic effects in Parkinson’s disease
Since four decades ago, several clinical studies have been reporting
that acute and chronic administration of L-type Ca2+ Channel Blockers
(CCBs), such as nifedipine and verapamil, produces reduction in
peripheral vascular resistance and arterial pressure associated with an
increase in plasma noradrenaline levels and heart rate, typical eects
of sympathetic hyperactivity [9]. However, the cellular and molecular
mechanisms involved in this apparent sympathomimetic eect of the
Figure 1: Role of Ca2+/cAMP interaction in neurotransmitter release, including dopamine from central nervous system.
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L-type CCBs remained unclear for decades. In addition, experimental
studies using isolated tissues richly innervated by sympathetic nerves
showed that neurogenic responses were completely inhibited by
L-type CCBs in high concentrations (>1 μmol/L), but paradoxically
potentiated in concentrations below 1 μmol/L [10-12]. During almost
four decades, these enigmatic phenomena remained unclear. In
2013, we discovered that this paradoxical increase in sympathetic
activity produced by L-type CCBs is due to Ca2+/cAMP interaction
[2-4]. en, the pharmacological manipulation of the Ca2+/cAMP
interaction produced by combination of the L-type CCBs used in the
antihypertensive therapy, and cAMP accumulating compounds used
in the anti-depressive therapy such as rolipram, could represent a
potential cardiovascular risk for hypertensive patients due to increase
in sympathetic hyperactivity. In contrast, this pharmacological
manipulation could be a new therapeutic strategy for increasing
neurotransmission in the psychiatric disorders, such as Parkinson’s
disease.
In addition, several studies have been demonstrating pleiotropic
eects of CCBs. CCBs, like nifedipine, genuinely have pleiotropic
eects [13]. Ca2+ channels are important regulators of central nervous
system, and their dysfunction can give rise to pathophysiological
conditions as psychiatric conditions such as epilepsy, pain and autism
[13]. In the nervous system, CCBs have been emerging as potential
therapeutic avenues for pathologies such as Parkinson’s disease [13].
However, the molecular mechanisms involved in these pleiotropic
eects remain under debate. Dierent mechanisms have been
proposed, but the exact mechanisms are still uncertain.
Importance of pharmacological modulation of Ca2+/cAMP
interaction in the treatment of Parkinson’s disease and
other neurodegenerative diseases
In contrast to adverse eects produced by combination of L-type
CCBs with cAMP accumulating compounds in the cardiovascular
diseases, the pharmacological implications of the Ca2+/cAMP
interaction produced by this drug combination could be used to
enhance neurotransmission [2-4].
Considering our model in which increment of [cAMP]c
stimulates Ca2+ release from ER (Figure 1), it may be plausible that the
therapeutic use of the PDE inhibitor rolipram [14,15], in combination
with low doses of verapamil to increase neurotransmission (Figure
1) in the areas of central nervous system involved in neurological/
psychiatric disorders in which neurotransmission is reduced,
including Parkinson’s disease. is new pharmacological strategy for
the treatment of psychiatric disorders could increase the therapeutic
ecacy and reduce the adverse eects of the medicines currently
used for treating Parkinson’s disease. Considering that CCBs
genuinely exhibit cognitive-enhancing abilities and reduce the risk
of neurodegenerative diseases like Parkinson’s disease [13]; and
that the mechanisms involved in these pleiotropic eects are largely
unknown. en, whether Ca2+/cAMP interaction is involved in such
eects deserves special attention.
In addition, considering [Ca2+]c elevation could contribute to
both: negatively to neuroprotective eects and positively to exocytosis,
it may be plausible the therapeutic use of the PDEs inhibitors
[14,15] for antiparkinsonism purposes. en, pharmacological
interference of the Ca2+/cAMP interaction produced by combination
of L-type CCBs and cAMP-accumulating compounds could
enhance antiparkinsonism response and reduce clinical symptoms
of neurodegenerative diseases. us, the association of currently
medicines could enhance antiparkinsonism treatments. For
example: the association of Levodopa with CCBs or rolipram could
dramatically improve typical antiparkinsonism medicines, mainly
by reducing their adverse eects and increasing their eectiveness.
is new pharmacological strategy could be alternatively used for
treatment of the symptoms of neurodegenerative diseases.
Conclusion
e diagnosis of neurodegenerative diseases like Parkinson’s
disease 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 Parkinson’s disease symptoms,
targeting potential risk factors aiming to decrease incidence of
this neurodegenerative disease is an important public health issue.
Finally, novel strategies to treat Parkinson’s diseases, throughout
our recent discovery entitled “calcium paradox” phenomenon due
to Ca2+/cAMP interaction, could greatly contribute to enhance
therapeutic strategies for increasing neuroprotection. us, the
association of typical antiparkinsonism medicines with CCBs or
rolipram could dramatically improve antiparkinsonism therapies,
mainly by reducing adverse eects and improving eectiveness of
these currently medicines [16].
References
1. Salat D, Noyce AJ, Schrag A, Tolosa E. Challenges of modifying disease
progression in prediagnostic Parkinson’s disease. Lancet Neurol. 2016; 15:
637-648.
2. Caricati-Neto A, Garcia AG, Bergantin LB. Pharmacological implications of
the Ca2+/cAMP signalling interaction: from risk for antihypertensive therapy to
potential benecial for neurological and psychiatric disorders. Pharmacol Res
Perspect. 2015; 3: e00181.
3. Bergantin LB, Souza CF, Ferreira RM, Smaili SS, Jurkiewicz NH, Caricati-
Neto A, et al. Novel model for “calcium paradox” in sympathetic transmission
of smooth muscles: role of cyclic AMP pathway. Cell Calcium. 2013; 54: 202-
212.
4. Bergantin LB, Jurkiewicz A, Garcia AG, Caricati-Neto A. A Calcium Paradox in
the Context of Neurotransmission. Journal of Pharmacy and Pharmacology.
2015; 3: 253-261.
5. Hayes MW, Fung VS, Kimber TE, O’Sullivan JD. Current concepts in the
management of Parkinson disease. Med J Aust. 2010; 192: 144-149.
6. Douglas WW, Rubin RP. The role of calcium in the secretory response of the
adrenal medulla to acetylcholine. J Physiol. 1961; 159: 40-57.
7. Baker PF, Knight DE. Calcium-dependent exocytosis in bovine adrenal
medullary cells with leaky plasma membranes. Nature. 1978; 276: 620-622.
8. Chern YJ, Kim KT, Slakey LL, Westhead EW. Adenosine receptors activate
adenylate cyclase and enhance secretion from bovine adrenal chromafn
cells in the presence of forskolin. J Neurochem. 1988; 50: 1484-1493.
9. Grossman E, Messerli FH. Effect of calcium antagonists on sympathetic
activity. Eur Heart J. 1998.
10. Kreye VA, Luth JB. Proceedings: verapamil-induced phasic contractions of
the isolated rat vas deferens. Naunyn Schmiedebergs Arch Pharmacol. 1975.
11. French AM, Scott NC. A comparison of the effects of nifedipine and verapamil
on rat vas deferens. Br J Pharmacol. 1981; 73: 321-323.
12. Moritoki H, Iwamoto T, Kanaya J, Maeshiba Y, Ishida Y, Fukuda H. Verapamil
Austin Neurol & Neurosci 1(2): id1009 (2016) - Page - 04
Bergantin LB Austin Publishing Group
Submit your Manuscript | www.austinpublishinggroup.com
enhances the non-adrenergic twitch response of rat vas deferens. Eur J
Pharmacol. 1987; 140: 75-83.
13. Zamponi GW. Targeting voltage-gated calcium channels in neurological and
psychiatric diseases. Nat Rev Drug Discov. 2016; 15: 19-34.
14. Li YF, Cheng YF, Huang Y, Conti M, Wilson SP, O’Donnell, et al.
Phosphodiesterase-4D knock-out and RNA interference-mediated knock-
down enhance memory and increase hippocampal neurogenesis via
increased cAMP signaling. J Neurosci. 2011; 31: 172-183.
15. Xiao L, O’Callaghan JP, O’Donnell JM. 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.
2011; 338: 641-647.
16. Bergantin LB, Caricati-Neto A. Challenges for the pharmacological treatment
of neurological and psychiatric disorders: Implications of the Ca2+/cAMP
intracellular signalling interaction. European Journal of Pharmacology. 2016;
788: 255-260.
Citation: Bergantin LB and Caricati-Neto A. Novel Insights for Therapy of Parkinson’s disease: Pharmacological
Modulation of the Ca2+/cAMP Signalling Interaction. Austin Neurol & Neurosci. 2016; 1(2): 1009.
Austin Neurol & Neurosci - Volume 1 Issue 2 - 2016
Submit your Manuscript | www.austinpublishinggroup.com
Bergantin et al. © All rights are reserved
