Pharmacological modulation of neural Ca 2+ /camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

Abstract

Alzheimer's disease (AD) is a debilitating neuropsychiatric disorder characterized by the multifaceted decline in cognitive and behavioral functions. Due to the multifaceted nature of AD pathology and our limited understanding on its etiology, AD is difficult to be treated with currently available pharmaceuticals. Then, new therapeutic strategies for AD have been proposed. Since 1975, several clinical studies have reported that L-type Ca 2+ channel blockers (CCBs) used in anti-hypertensive therapy produces increase of plasma catecholamine levels and tachycardia, typical symptoms of sympathetic hyperactivity. Despite these adverse effects of CCBs have been initially attributed to adjust reflex of arterial pressure, during almost four decades these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical sympathetic hyperactivity produced by CCBs results from the increase of catecholamines release from sympathetic nerves and adrenal chromaffin cells due to its modulatory action on the interaction between intracellular signaling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP signalling interaction). In addition, we discovered that the modulation of this interaction may stimulate neuroprotective response due to activation of cell survival pathways mediated by cAMP-responsive element binding protein (CREB). Then, the pharmacological modulation of Ca 2+ /cAMP signalling interaction by combined use of L-type CCBs and cAMP-enhancer compounds could be a more efficient and safer therapeutic strategy to produce increase of cholinergic neurotransmission and neuroprotection, attenuating cognitive deficit in AD patients.

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Mini Review
Journal of Systems and Integrative Neuroscience
J Syst Integr Neurosci, 2017 doi: 10.15761/JSIN.1000185 Volume 3(6): 1-4
ISSN: 2059-9781
Pharmacological modulation of neural Ca2+/camp signaling
interaction as therapeutic goal for treatment of Alzheimer´s
disease
Afonso Caricati-Neto and Leandro Bueno Bergantin*
Department of Pharmacology - Universidade Federal de São Paulo - Escola Paulista de Medicina, Brazil
Abstract
Alzheimer's disease (AD) is a debilitating neuropsychiatric disorder characterized by the multifaceted decline in cognitive and behavioral functions. Due to the
multifaceted nature of AD pathology and our limited understanding on its etiology, AD is dicult to be treated with currently available pharmaceuticals. en,
new therapeutic strategies for AD have been proposed. Since 1975, several clinical studies have reported that L-type Ca2+ channel blockers (CCBs) used in anti-
hypertensive therapy produces increase of plasma catecholamine levels and tachycardia, typical symptoms of sympathetic hyperactivity. Despite these adverse eects
of CCBs have been initially attributed to adjust reex of arterial pressure, during almost four decades these enigmatic phenomena remained unclear. In 2013, we
discovered that this paradoxical sympathetic hyperactivity produced by CCBs results from the increase of catecholamines release from sympathetic nerves and adrenal
chroman cells due to its modulatory action on the interaction between intracellular signaling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP signalling
interaction). In addition, we discovered that the modulation of this interaction may stimulate neuroprotective response due to activation of cell survival pathways
mediated by cAMP-responsive element binding protein (CREB). en, the pharmacological modulation of Ca2+/cAMP signalling interaction by combined use of
L-type CCBs and cAMP-enhancer compounds could be a more ecient and safer therapeutic strategy to produce increase of cholinergic neurotransmission and
neuroprotection, attenuating cognitive decit in AD patients.
Correspondence to: Bergantin LB, Department of Pharmacology - Universidade
Federal de São Paulo - Escola Paulista de Medicina, Laboratory of Autonomic
and Cardiovascular Pharmacology – 55 11 5576-4973, Rua Pedro de Toledo,
669 – Vila Clementino, São Paulo – SP, Brazil, CEP: 04039-032, E-mail:
leanbio39@yahoo.com.br
Key words: Ca2+/cAMP signalling interaction, neurotransmission,
neuroprotection, Alzheimer´s disease.
Received: November 08, 2017; Accepted: December 02, 2017; Published:
December 05, 2017
Introduction
Since 1970´s, several clinical studies have reported that acute and
chronic administration of L-type Ca2+ channel blockers (CCBs) in
hypertensive patients, such as nifedipine and verapamil, decreased
arterial pressure but produced typical symptoms of sympathetic
hyperactivity such as tachycardia, and increment of catecholamine
plasma levels [1]. Despite these adverse eects of CCBs have been
initially credited to adjust reex of arterial pressure, the cellular and
molecular mechanisms involved in these CCBs-eects remained
unclear for decades. Our previous studies performed in isolated
tissues richly innervated by sympathetic nerves (rat vas deferens),
to exclude the inuence of adjusting reex, showed that neurogenic
responses were completely inhibited by L-type CCBs in high
concentrations (>1 μmol/L), but unexpectedly and paradoxically
potentiated in concentrations below 1 μmol/L, characterizing CCBs-
induced sympathetic hyperactivity [2-4]. During almost four decades,
these paradoxical eects of CCBs named by us as “calcium paradox”
remained unclear.
In 2013, we discovered that this paradoxical sympathetic
hyperactivity produced by L-type CCBs is due to its modulatory
action on the interaction between the intracellular signalling pathways
mediated by Ca2+ and cAMP (Ca2+/cAMP signalling interaction).
Our studies have showed that the pharmacological modulation of
the Ca2+/cAMP signalling interaction by combined use of L-type
CCBs and compounds which increase cytosolic cAMP concentration
([cAMP]c), named cAMP-enhancer compounds, could be useful to
increase neurotransmission, and neuroprotection in neurological and
psychiatric disorders, such as Alzheimer´s diseases (AD) [5-8].
Current therapy to treat Alzheimer´s disease (AD)
Accumulation of the β-amyloid peptide (Aβ) in brain tissues
represents the pathological status of AD [9,10]. According to the
amyloid hypothesis, disruption of homeostatic processes causes
overproduction of Aβ. Age-related factors could favor a metabolic
alteration, favoring the amyloidogenic processing [9,10]. e neurotoxic
potential of the Aβ results from its potential to favor aggregation. is
process, along with a reduction of Aβ removal from the brain, leads
to the extracellular accumulation of Aβ, and the subsequent activation
of neurotoxic cascades, that ultimately leads to neuronal dysfunction
and cellular death [9,10]. e relevance of the early diagnosis of AD
relies on the hypothesis that pharmacological interferences on disease-
modifying complexes are more likely to produce clinically relevant
rules if started early enough in the continuum towards dementia
[9,10]. erapies leading the change of amyloid-related cascades may
be viewed as promising plans to attenuate or even to revert dementia
[10]. erefore, the cumulative knowledge on the pathogenesis of AD

Caricati-Neto A (2017) Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease
J Syst Integr Neurosci, 2017 doi: 10.15761/JSIN.1000185 Volume 3(6): 2-4
derived from basic science models will hopefully be translated into
clinical practice in the upcoming years. Other targets relevant to AD
have also been considered in the last years for making multitarget
compounds [11,12].
In addition to what has been discussed above, acetylcholinesterase
(AChE) is another important target to treat the pathogenesis of
AD (cholinergic dysfunction hypothesis). Considering the current
hypothesis of accretion of the Aβ in AD, this relies in the reduction of
acetylcholine release in central cholinergic nervous system involved in
cognitive function. us, the inhibition of acetylcholine degradation
by AChE is a potential goal to treat AD [11,12]. Deleterious excess Ca2+
inux is also another constituent seen in aging and neurodegenerative
diseases [13]. us, hybrid compounds having the moieties of tacrine
(potent inhibitor of brain and peripheral AChE), and nimodipine
(L-type CCBs) have been synthetized [11,12]. In addition, galantamine,
a mild AChE inhibitor, and an allosteric ligand of nicotinic receptors,
has been used to progress enhancing cognition and behavior in
patients with AD [14]. Finally, N-methyl-D-aspartat (NMDA) receptor
antagonist (memantine) has also been proposed to treat this disease
[15]. Besides the current medicines available nowadays in clinics,
new insights for more ecient pharmacological treatments of AD are
clearly needed.
Role of the Ca2+/cAMP signalling interaction in neuro-
transmission
Many experiments studies initiated decades ago, using adrenal
chroman cells as cellular model, established the notion of stimulus-
secretion coupling to explain transmitter release from central and
peripheral neurons. In 1970´s, it was discovered that a rise in the
cytosolic Ca2+ concentration ([Ca2+]c) is an elementary requirement
to trigger transmitter release from adrenal chroman cells [16].
In 1990´s, it was showed a direct relationship between rise in [Ca2+]
c and rapid transmitter release from adrenal chroman cells [17]. It
was also showed that increase of [cAMP]c in adrenal chroman cells
due to activation of adenylate cyclase by forskolin enhances release of
secretory vesicles containing transmitters (catecholamines, purines
and other substances) [18]. ese ndings support that both Ca2+
and cAMP are involved in the regulation of neurotransmitter release
at many peripheral and central synapses of mammals, including
sympathetic synapses.
In 2013, we discovered that neurotransmitter release from
sympathetic neurons is nely regulated by interaction between
intracellular signalling pathways mediated by Ca2+ and cAMP, named
Ca2+/cAMP signalling interaction [6]. In fact, the hypothesis for a
suitable Ca2+/cAMP signalling interaction has been widely studied in
dierent cell types and tissues. is interaction results in synergistic
actions of these intracellular messengers on cell functions regulated
by adenylyl cyclases (ACs), or phosphodiesterases (PDEs) [5-8]. e
Ca2+/cAMP signalling interaction has particularly been extensively
studied at the endoplasmic reticulum (ER) Ca2+ channels, such as
ER-Ca2+ channels regulated by ryanodine receptors (RyR) [5-8].
Our studies established that Ca2+/cAMP signalling interaction play
an important role in neurotransmitter release regulation in neurons
and neuroendocrine cells [5-8]. us, pharmacological modulation of
this interaction produced by L-type CCBs and cAMP-enhancer drugs
could be useful to treat neurological and psychiatric disorders resulting
from neurotransmitter release decit, such as AD, Parkinson's disease
and depression [5-8].
Role of the Ca2+/cAMP signalling interaction in neuro-
protection
It is well established that cytosolic Ca2+ overload is directly involved
in neuronal death in various neurodegenerative diseases, including
AD and Parkinson's diseases [5-8]. Recently, it was showed that
the treatment with L-type CCBs, such as isradipine, reduces motor
symptoms and attenuates progressive death of dopamine neurons
from substantia nigra in animal model of Parkinson's disease [19].
It was showed that isradipine produces a dose-dependent sparing of
dopaminergic bers, and cell bodies at concentrations achievable
in humans [20], suggesting that L-type CCBs are potentially viable
neuroprotective agents for Parkinson's disease. A phase II clinical trial
published in 2016 showed that treatment with isradipine was safely
tolerated to reduce motor symptoms by patients with Parkinson's
disease [20]. In addition, a 10-year follow-up study (2000 to 2010),
involving 82,107 hypertensive patients of more than 60 years of age,
showed that use of L-type CCBs reduced blood pressure, and risk of
dementia in hypertensives patients, suggesting that these drugs could
be clinically used to treat AD [21]. ese ndings reinforced the idea
that attenuation of cytosolic Ca2+ overload produced by L-type CCBs
due to blockade of Ca2+ inux through L-type voltage-activated Ca2+
channels (VACC) could be an excellent pharmacological strategy to
attenuate, or prevent, neuronal death in neurodegenerative diseases,
such as AD and Parkinson's disease.
As previously mentioned, blockade of the L-type VACC by CCBs
reduces Ca2+ inux and [Ca2+]c, increasing ACs activity and [cAMP]
c [5-8]. is functional Ca2+/cAMP signalling interaction regulates
various cellular responses, including neurotransmitter release [5-
8]. Many studies showed that increase of [cAMP]c stimulates
neuroprotective response attenuating neuronal death due probably to
activation of cellular survival pathways mediated by cAMP-response
element binding protein (CREB) [22-24]. In this way, pharmacological
modulation of the Ca2+/cAMP signalling interaction by combined
use of L-type CCBs and cAMP-enhancer compounds could stimulate
neuroprotective response due to increase of [cAMP]c and attenuation
of cytosolic Ca2+ overload [5-8]. us, pharmacological modulation of
this interaction could be a new neuroprotective therapeutic strategy to
slow the progression of neurodegenerative diseases, such as AD and
Parkinson's disease.
Pharmacological modulation of neural Ca2+/cAMP sig-
nalling interaction as therapeutic goal for treatment of
Alzheimer´s disease (AD)
Our discovery of the involvement of the Ca2+/cAMP signalling
interaction in the neurotransmission, and neuroprotection, has produced
important advances in the understanding of the pathophysiology and
pharmacology of neurological and psychiatric disorders [5-8]. ese
advances allowed us to propose that pharmacological modulation of
the Ca2+/cAMP signalling interaction produced by combined use of the
L-type CCBs such as isradipine (usually indicated in antihypertensive
therapy), and cAMP-enhancer compounds such as rolipram
(usually indicated in anti-depressive therapy), could represent a new
therapeutic strategy for enhancing neurotransmission, and producing
neuroprotection in the neurodegenerative diseases, such as AD.
Our studies suggest that pharmacological modulation of the Ca2+/
cAMP signalling interaction by combined use of the L-type CCBs and
cAMP-enhancer compounds induces enhance of neurotransmission
due to increase of neurotransmitter release mediated by Ca2+ release

Caricati-Neto A (2017) Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease
J Syst Integr Neurosci, 2017 doi: 10.15761/JSIN.1000185 Volume 3(6): 3-4
from ER stimulated by cAMP [5-8]. is Ca2+ release from ER produces
increase number of secretory vesicles docked in plasma membrane,
increasing neurotransmitter release [5-8]. en, pharmacological
modulation of the Ca2+/cAMP signalling interaction could be a new
therapeutic strategy to treat neurological and psychiatric disorders
resulting from neurotransmitter release decit. In addition,
pharmacological modulation of the Ca2+/cAMP signalling interaction
could reduce neuronal death in neurodegenerative disease due to
attenuation of cytosolic Ca2+ overload, increase of [cAMP]c and
stimulation of cell survival pathways mediated by CREB [22-24]. us,
pharmacological modulation of Ca2+/cAMP signalling interaction
could be a new neuroprotective therapeutic strategy to slow the
progression of neurodegenerative diseases, such as AD [5-8,25,26].
Our proposal of pharmacological modulation of the Ca2+/
cAMP signalling interaction could open a new avenue for the drug
development more eective and safer to reduce clinical symptoms of
neurological and psychiatric disorders resulting from neurotransmitter
release decit, and neuronal death triggered by cytosolic Ca2+ overload,
such as AD [5-8,25,26]. Figure 1 show how pharmacological modulation
of the Ca2+/cAMP signalling interaction using L-type CCBs and cAMP-
enhancer compounds could produce increase of neurotransmission
and neuroprotection.
Figure 1. Increase of neurotransmitter release and attenuation of neuronal death produced by pharmacological modulation of the Ca2+/cAMP signalling interaction by combined use of L-type
Ca2+ channel blockers (CCBs) and cAMP-enhancer compounds, such as phosphodiesterase (PDE) inhibitors.

Caricati-Neto A (2017) Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease
J Syst Integr Neurosci, 2017 doi: 10.15761/JSIN.1000185 Volume 3(6): 4-4
Conclusion
Our recent discovery of role of the Ca2+/cAMP signalling interaction
in the neurotransmission and neuroprotection could promote
important advances in the pathophysiology and pharmacology of the
neurological and psychiatric disorders. ese advances can contribute
to drug development more eective and safer to attenuate clinical
symptoms of neurological and psychiatric disorders, such as AD.
Disclosure statement
Caricati-Neto and Bergantin thank the continued nancial support
from CAPES, CNPq and FAPESP (Bergantin´s Postdoctoral Fellowship
FAPESP #2014/10274-3).
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