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Increase of neurotransmission produced by pharmacological modulation of neural Ca /cAMP signaling 2+ interaction. (A) Records showing that contractile responses mediated by neurotransmitter released from sympathetic nerves by means electrical field stimulation in rat vas deferens (neurogenic contractions) were significantly reduced by L-type CCBs (verapamil) in high concentrations (>10 M), but -6 paradoxically increased in concentrations below 10 M, -6 characterizing CCBs-induced sympathetic hyperactivity. This increase of neurogenic contractions by verapamil (<10 M) was -6 potentiated by pre-treatment of isolated tissue with cAMPenhancer compounds, such as rolipram 10 M (B), IBMX 10 M -7 -6 (C) and forskolin 10 M (D). This potentiation by cAMP-enhancer -7 compounds was prevented by inhibition of ACs with SQ 22536 (Data not showed). Each point below the record represents molar concentration of verapamil (interval of 0.5 log unity). Each line below the record represents incubation time with cAMP-enhancer compounds. Representative records extracted from Bergantin et al. (2013). Role of the neural Ca /cAMP signaling interaction in 2+
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Abstract It is well established that an imbalance of neuronal Ca2+ homeostasis contributes to the pathogenesis of neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's (PD) diseases. Therefore, regulation of neuronal Ca2+ homeostasis may represent a new therapeutic strategy of these diseases. Our recent discovery of the involvement o...
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... discovery strengthened the idea that the exocytosis of secretory vesicles containing transmitters from neurons and neuroendocrine cells is finely regulated by neural Ca /cAMP signaling interaction ( Bergantin et al., 2013;2+ Caricati-Neto et al., 2015;Bergantin and Caricati-Neto, 2016a, 2016b, 2016c, 2016d). Figure 1 shows the potentiation by cAMP-enhancer compounds of the CCBs-induced sympathetic hyperactivity. ...
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It is well recognized that an imbalance of intracellular Ca 2+ homeostasis contributes to the pathogenesis of neurodegenerative diseases, such as Alzheimer's (AD). Therefore, regulation of intracellular Ca 2+ homeostasis may represent a new target for treatment of this disease. Our recent discovery of the participation of the interaction between in...
Our discovery of the involvement of the interaction between intracellular signalling pathways mediated by Ca2+ and cAMP (Ca 2+ /cAMP interaction) in the neurotransmission and neuroprotection has produced new avenues in the understanding of the cellular and molecular mechanisms involved in the pathogenesis of neurological and psychiatric disorders,...
It is well recognized that an imbalance of intracellular Ca2+ homeostasis contributes to the pathogenesis of neurodegenerative diseases, such as Alzheimer's (AD). Therefore, regulation of intracellular Ca2+ homeostasis may represent a new target for treatment of this disease. Our recent discovery of the participation of the interaction between intr...
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... Presently, the findings from preclinical in vivo neurotoxin-influenced Parkinson's disease models are not sufficient to predict whether Ca v 1.2, Ca v 1.3, or both isoforms are responsible for the proposed toxicity of Ca 2+ ion. Calcium-mediated side effects like peripheral edema and/or hypotension, in clinical trials, limit long-term treatment of Parkinson's disease with large doses of dihydropyridines providing a strong support for efforts to discover calcium channel selective inhibitors (Surmeier et al. 2017;Yang et al. 2014a, b;Caricati-Neto and Bergantin 2016). ...
Calcium channel plays a very crucial role in the regulation of various vital functions of the body. The effects and modes of action of various drugs on calcium channels have been outlined with every detail. The pharmacology of various subunits and subtypes of this channel has been discussed in view of drug development in the near future. The role of Cav1 channel in health problems such as Parkinson’s disease, cardiovascular diseases, subtypes of Cav2 channels in terms of G-protein inhibition and synaptic vesicle release, Cav3 channels for peptide toxins, and α2δ ligands in amino acid transportation and synaptic transmission has been highlighted in the literature. Diseases like obesity, epilepsy, and anxiety can be treated easily by targeting the T-type calcium channel which is one of the best potential therapeutic targets for the aforesaid diseases. In epilepsy and neuropathic pain, α2δ subunit is the most prominent area of therapeutic target by the gabapentinoid drugs. Thus, scientific research on calcium channel pharmacology may become revolutionary in the management of various chronic diseases. In this chapter, all possible attention has been given to describe the super selectivity of different subtypes of calcium channels by focusing on isoforms of channels and biophysical properties in various target tissues.
... Of course not, and we proved it! Our group has been one of the pioneers in establishing that the so-called Ca 2+ /cAMP signalling interaction is a fundamental cellular process for mammalians [1][2][3][4][5][6][7][8][9][10]. This interaction has 'unlocked' a new 'paradigm' to the drug development for the treatment of diseases like Alzheimer's and others, related to the neurotransmitter release deficit, now including possible cancer. ...
... Our group has been pioneering in establishing that the manipulation of Ca 2+ /cAMP signalling interaction could be a better therapeutic 'cellular method' for increasing neurotransmission in psychiatric disorders, and stimulating neuroprotection for combating neurodegenerative diseases, such as Alzheimer's disease. As the activity of adenylyl cyclase (AC) is controlled by Ca 2+ , the decrease of [Ca 2+ ]c achieved by L-type CCBs promotes an increase of activity of ACs, and rise of [cAMP]c (Ca 2+ /cAMP signalling interaction) [1][2][3][4][5][6][7][8][9][10]. Isn't it spectacular? ...
Our group has been pioneering in exploring that the pharmacological handling of Ca 2+/ cAMP signalling interaction could be a better therapeutic method for increasing neurotransmission in psychiatric disorders, and stimulating neuroprotection for combating neurodegenerative diseases, such as Alzheimer´s disease. Indeed, Ca 2+ is a classic intracellular second messenger, now well recognized as a ubiquitous molecule that controls several processes, including gene transcription, cell cycle regulation, mobility, apoptosis, neurotransmitter release and muscle contraction. In addition, cAMP, another vital intracellular messenger, modulates since cardiac contraction to neurotransmitter release. Do these intracellular messengers´work´ independently? Of course not, and we demonstrated it! Through groundbreaking experiments (including one by accident!), our group discovered that the paradoxical effects (e.g. reduction of intracellular Ca 2+ concentration, and enhancing of neurotransmitter release?!) produced by L-type Ca 2+ channel blockers (CCBs) resulted from interferences on the Ca 2+ / cAMP signalling interaction. Considering the widely use of CCBs as antihypertensive drugs, and for combating arrhythmia, the elucidation of these paradoxical effects proved to be very important (specially for clinical reasons). How does this history correlate to cancer field? Considering the notion that Ca 2+ /cAMP signalling interaction is a fundamental cellular process, which exists in many cell types, whether this interaction may be a novel therapeutic target to alter cancer tumor growth, angiogenesis and metastasis, without affecting normal cell physiology deserves special consideration. Thus, this editorial article highlights the latest advances made by our group in the field of Ca 2+ /cAMP signalling interaction.
... Our discovery that the interaction between Ca 2+ and cAMP signalling pathways plays a role in the synaptic transmission, including protection against neurodegeneration, has supported thoughtful ideas about the neurobiology of the neurological disorders, opening a large pathway for the improvement of new pharmacological approaches for handling with these disorders [1][2][3][4][5][6][7][8][9][10]. The augmentation in the lifetime quality of the global population has amplified the prevalence of senile people. ...
... Thus, by increasing cAMP levels, this intracellular messenger may augment the release of Ca 2+ from endoplasmic reticulum. Indeed, Ca 2+ is vital for the neurotransmitter release process, participating in virtually all the earlier mentioned steps [1][2][3][4][5][6][7][8][9][10]. In fact, the pioneering work of Katz and collaborators in the early 1950s has demonstrated that an increase in [Ca 2+ ] is the immediate trigger for neurotransmitters/hormones release from neurons, and neuroendocrine cells. ...
Editorial: Our discovery that the interaction between Ca 2+ and cAMP signalling pathways plays a role in the synaptic transmission, including protection against neurodegeneration, has supported thoughtful ideas about the neurobiology of the neurological disorders, opening a large pathway for the improvement of new pharmacological approaches for handling with these disorders [1-10]. The augmentation in the lifetime quality of the global population has amplified the prevalence of senile people. Nonetheless, it has increased the incidence of neurological disorders, such as Alzheimer's disease (AD) and Parkinson's (PD) disease. From elementary science, we now know that a disbalance of intracellular Ca 2+ homeostasis is correlated with the neurobiology of neurological disorders, such as AD and PD. Four years ago, we revealed that the interaction between Ca 2+ and cAMP signalling pathways plays a role in the modulation of neurotransmitters release from sympathetic neurons [9]. In addition, we revealed that the manipulation of the interaction between Ca 2+ and cAMP signalling pathways could be used to attenuate the degeneration of neurons in the neurological disorders, resulted from cytosolic Ca 2+ excess [10]. This novel proposal involves medicines already approved, and clinically safe, from non-neurodegenerative treatment indications. These ideas have been widely debated in numerous cited international articles of my own authorship (>40), book chapters and in a worldwide-recognized book [5]. Briefly, we revealed that L-type Ca 2+ channel blockers (CCBs) increase cAMP levels. These CCBs-effects can be enhanced by cAMP-stimulating compounds (like phosphodiesterase inhibitors). Indeed, the essential mechanisms by which the interaction between Ca 2+ and cAMP signalling pathways may rise the neurotransmitter release are due: increasing the amount of neurotransmitter in the secretory vesicles, and enhancing the frequency of neurotransmitter release. Thus, by increasing cAMP levels, this intracellular messenger may augment the release of Ca 2+ from endoplasmic reticulum. Indeed, Ca 2+ is vital for the neurotransmitter release process, participating in virtually all the earlier mentioned steps [1-10]. In fact, the pioneering work of Katz and collaborators in the early 1950s has demonstrated that an increase in [Ca 2+ ] is the immediate trigger for neurotransmitters/hormones release from neurons, and neuroendocrine cells. Physiologically, this increase of [Ca 2+ ]c is primarily started by activation of nicotinic cholinergic receptors on surface of neuronal body of sympathetic neurons (postganglionic), and adrenal chromaffin cells, by ACh from ending nerves of preganglionic neurons, derived from thoracolumbar portion of medulla [11,12]. In the adrenal chromaffin cells, this event triggers release of adrenaline, and noradrenaline, from adrenal chromaffin cells into the bloodstream. In the postganglionic sympathetic neurons, this event triggers release of noradrenaline in the sympathetic neuro-effector synapse. In these synapses, the adrenaline and noradrenaline interact with adrenoceptors on surface of effector cells (smooth and cardiac muscle cells, and exocrine cells) producing a series of physiological reactions characterized as "fight or flight" responses, such as elevation of blood pressure, acceleration of heart rate and hyperglycemia. In mammals, the catecholamines synthesized by the...
... Thus, we proposed that the neuronal death resulting from cytosolic Ca 2+ overload associated to neurodegenerative disorders could be attenuated or prevented in response to stimulation of the cellular survival pathways mediated by cAMP/PKA/CREB signaling by means the pharmacological modulation of the Ca 2+ /cAMP signaling interaction [7][8][9][10][11][12][13][14]. Thus, our discovery of the role of the Ca 2+ / cAMP signaling interaction in neurotransmission and neuroprotection, and its pharmacological modulation, may open a large avenue for the development of a new therapeutic strategy for neurodegenerative disorders such as AD [7][8][9][10][11][12][13][14]21]. Then, in this review we will discuss how the pharmacological modulation of the Ca 2+ /cAMP signaling interaction could be a new therapeutic strategy to treat the cognitive deficit in AD. ...
... For example: the association of Levodopa with CCBs or rolipram could dramatically improve typical antiparkinsonism medicines, mainly by reducing their adverse effects and increasing their effectiveness. This new pharmacological strategy could be alternatively used for treatment of the symptoms of neurodegenerative diseases [16][17][18][19][20][21][22][23]. ...
... 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 Ca 2+ /cAMP interaction, could greatly contribute to enhance therapeutic strategies for increasing neuroprotection [16][17][18][19][20][21][22][23]. Thus, the association of typical antiparkinsonism medicines with CCBs or rolipram could dramatically improve antiparkinsonism therapies, mainly by reducing adverse effects and improving effectiveness of these currently medicines [16][17][18][19][20][21][22][23]. ...
... Finally, novel strategies to treat Parkinson´s diseases, throughout our recent discovery entitled "calcium paradox" phenomenon due to Ca 2+ /cAMP interaction, could greatly contribute to enhance therapeutic strategies for increasing neuroprotection [16][17][18][19][20][21][22][23]. Thus, the association of typical antiparkinsonism medicines with CCBs or rolipram could dramatically improve antiparkinsonism therapies, mainly by reducing adverse effects and improving effectiveness of these currently medicines [16][17][18][19][20][21][22][23]. ...
Since 70´s, the sympathetic hyperactivity due to increment of catecholamine plasma levels is the main adverse effect reported by hypertensive patients that use L-type Ca 2+ channel blockers (CCBs). Our discovery of the involvement of interaction between the intracellular signalling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP interaction) revealed that the sympathetic hyperactivity was resulting of increase of transmitter release from sympathetic neurons stimulated by CCBs due to its interference on the Ca 2+ /cAMP interaction. For the pharmacotherapy of Parkinson´s disease, new paths for the understanding of the cellular and molecular mechanisms involved in the pathogenesis of this disease can be achieved through this discovery. In this way, novel pathways for the development of new pharmacological strategies more effective for the treatment of Parkinson´s may be initiated.
... Undeniably, several studies showed that neuroprotective response can be achieved by increase of cytosolic cAMP concentration ([cAMP] c) [12][13][14][15][16][17][18][19]. In this way, we could propose that a rise of [cAMP]c by interfering in the Ca 2+ /cAMP interaction could attenuate neuronal death triggered by cytosolic Ca 2+ overload [12][13][14][15][16][17][18][19]. ...
... Undeniably, several studies showed that neuroprotective response can be achieved by increase of cytosolic cAMP concentration ([cAMP] c) [12][13][14][15][16][17][18][19]. In this way, we could propose that a rise of [cAMP]c by interfering in the Ca 2+ /cAMP interaction could attenuate neuronal death triggered by cytosolic Ca 2+ overload [12][13][14][15][16][17][18][19]. In conclusion, the pharmacological interference of the Ca 2+ /cAMP interaction produced by combined prescription 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 increasing neurotransmission in neurological and psychiatric disorders resulting from neurotransmitter release deficit, and/or neuronal death. ...
About 4 years ago, we showed that the paradoxical effects (sympathetic hyperactivity) induced by L-type voltage-activated Ca 2+ channels (VACC) blockers, named by us "calcium paradox" phenomenon, were potentiated by drugs which increase cytosolic cAMP concentration ([cAMP] c-enhancers), for example rolipram, IBMX and forskolin, indicating that the sympathetic hyperactivity induced by VACC blockers is due to interaction of the Ca 2+ /cAMP intracellular signaling pathways (Ca 2+ /cAMP interaction). Then, the pharmacological handling of this interaction produced by combined use of the L-type VACC blockers prescribed in the antihypertensive therapy, and [cAMP]c-accumulating compounds prescribed in the antidepressive therapy, could represent a potential cardiovascular deleterious effect for hypertensive patients due to stimulation of sympathetic hyperactivity. Then, we discussed the role of Ca 2+ /cAMP interaction for neurodegenerative diseases pharmacotherapy. In conclusion, this interaction could be a novel therapeutic target for drug development.
... Although the primary dysfunctions that lead to neurodegeneration and neuronal death in the brain of HD patients are not fully understood, recent evidences indicate that an imbalance in the intracellular calcium (Ca 2+ ) homeostasis in neuronal cells is directly involved in neurodegenerative process that cause motor and cognitive dysfunctions [9,10]. It is important to note that the Ca 2+ is an intracellular messenger involved in the regulation of the multiple cellular processes, including cell proliferation and differentiation, neurotransmitter release, hormone secretion, cell excitation and plasticity, and others [11][12][13][14][15][16][17][18][19]. However, an imbalance in the intracellular Ca 2+ homeostasis could result in loss of cellular function and death due to cytosolic Ca 2+ overload [9,10]. ...
... Neurons are excitable cells that require extremely precise spatial-temporal control of Ca 2+ -dependent processes because this ion regulates vital functions as synaptic plasticity. When these cells are depolarized, the Ca 2+ from the extracellular fluid enters into cytosol by the voltage-activated Ca 2+ channels (VACC), transiently increasing the cytosolic Ca 2+ concentration ([Ca 2+ ]c [11][12][13][14][15][16][17][18][19]. The nervous system expresses VACC with unique cellular and subcellular distribution and specific functions. ...
... The nervous system expresses VACC with unique cellular and subcellular distribution and specific functions. N-, P/Q-and L-type VACC are distributed at neuronal cells regulating neuronal excitability, neurotransmitter release, and gene expression [11][12][13][14][15][16][17][18][19]. Evidences obtained from natural mutants, knockout mice, and human genetic disorders indicate a fundamental role of some VACC in a wide variety of neurodegenerative disorders, including AD and PD [11][12][13][14][15][16][17][18][19]. ...
Caricati-Neto A, Bergantin LB. Huntington´s disease and the interaction between Ca 2+ and cAMP signaling pathways. J Pharmacol Res December-2017;1(1):17-24. Huntington disease (HD) is a neurodegenerative disease known by progressive motor, behavioral, and cognitive decline that culminates in the death. HD therapy is yet unsatisfactory. Chorea and psychiatric symptoms usually respond to pharmacotherapy. Recent advances in pathogenesis and newer biomarkers have promoted some progresses in HD therapy. It was suggested that an imbalance in the intracellular calcium (Ca 2+) homeostasis has a key role in neurodegenerative diseases. Recently, we showed that the interaction between intracellular signaling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP signaling interaction) plays as a key role in several cellular responses in mammalians, including neurosecretion and cell survival. Our studies showed that the pharmacological modulation of the Ca 2+ /cAMP signaling interaction by the combined use of the Ca 2+ channel blockers (CCB), and drugs that increase the intracellular concentration of cAMP (cAMP-enhancer compounds), increases synaptic neurotransmission and stimulates neuroprotective response. Thus, we have proposed that this new pharmacological strategy could open a new avenue for the drug development more effective and safer for treatment of the neurodegenerative diseases, including HD. Here, we discuss the perspectives of the pharmacological modulation of the Ca 2+ /cAMP signaling interaction as a new therapeutic strategy for HD.
... It is well established that the Ca 2+ finely regulates the AC activity, and consequently the [cAMP] c , virtually in all mammalian cells, characterizing the functional interaction between the intracellular signaling mediated by Ca 2+ and cAMP (Ca 2+ /cAMP signaling interaction) [25,26]. By means the pharmacological modulation of the Ca 2+ /cAMP signaling interaction, we discovered that this interaction rules an important participation in the different cellular response, including in neurotransmitter/hormone exocytosis and cellular survival [26][27][28][29][30]. The Ca 2+ /cAMP signaling interaction finely controls the [Ca 2+ ] c regulating the different steps of exocytosis, such as traffic and docking of secretory vesicle containing neurotransmitter and hormone [26][27][28][29][30]. ...
... By means the pharmacological modulation of the Ca 2+ /cAMP signaling interaction, we discovered that this interaction rules an important participation in the different cellular response, including in neurotransmitter/hormone exocytosis and cellular survival [26][27][28][29][30]. The Ca 2+ /cAMP signaling interaction finely controls the [Ca 2+ ] c regulating the different steps of exocytosis, such as traffic and docking of secretory vesicle containing neurotransmitter and hormone [26][27][28][29][30]. In addition, the Ca 2+ /cAMP signaling interaction participate in the regulation of cellular survival mediated by cAMP/PKA/CREB [26][27][28][29][30]. Bergantin [26][27][28][29][30]. ...
... The Ca 2+ /cAMP signaling interaction finely controls the [Ca 2+ ] c regulating the different steps of exocytosis, such as traffic and docking of secretory vesicle containing neurotransmitter and hormone [26][27][28][29][30]. In addition, the Ca 2+ /cAMP signaling interaction participate in the regulation of cellular survival mediated by cAMP/PKA/CREB [26][27][28][29][30]. Bergantin [26][27][28][29][30]. ...
Cancer is a major public health problem and the second leading cause of mortality around the world. Antitumor immunotherapy using monoclonal antibodies is considered selective and efficient in the treatment of different types of tumors, but its cost and toxic effects limit its application. Many tumor microenvironments, including lymphoma and carcinoma, are enriched in immune suppressive cells that contribute to immune exhaustion by means expression of inhibitory ligands, suppressive cytokines, and tumor-promoting factors. Antitumor therapies targeted to reduce the induction, recruitment, or suppressive activities of the immune cells have been investigated. New antitumor strategies using drugs targeted to intracellular signaling involved in cell proliferation and survival, angiogenesis, and metastasis have become promising in recent years. Thus, our discovery of the role of functional interaction between intracellular signaling pathways mediated by calcium ions (Ca 2+) and cyclic adenosine monophosphate (cAMP) (Ca 2+ /cAMP signaling interaction) in these cellular responses, opened a great avenue for the development of new antitumor therapeutic strategies. Here, we discuss how the combined use of monoclonal antibodies with drugs that modulate the Ca 2+ /cAMP signaling interaction to reduce tumor growth could be a potential strategy in the antitumor immunotherapy due to the increment of antitumor efficacy and reduction of adverse effects.
... Based on these findings, we have anticipated that the pharmacological regulation of the Ca 2+ /cAMP signalling interaction by combined use of the L-type CCBs and [cAMP]c-enhancer compounds could be a novel therapeutic goal for increasing neurotransmission in neurological, and psychiatric disorders, resulted from neurotransmitter release deficit and neuronal death [8][9][10][11]. This pharmacological strategy opens a novel pathway for the drug development more efficient for the treatment of Alzheimer´s and other neurodegenerative diseases [18][19][20][21][22][23][24]. ...
It is now well-established that the signalling pathways mediated by Ca 2+ and cAMP can interact (Ca 2+ /cAMP signalling interaction), thus playing a vital role in cellular processes of mammalians. In the neurology and medicine, it has opened novel opportunities for the development of pharmaceuticals more efficient, and safer, for treating neurodegenerative diseases. The solution for the so-called " calcium paradox " has been revealed 4 years ago, when we demonstrated the involvement of the Ca 2+ /cAMP signalling interaction in this enigma. The " calcium paradox " emerged 4 decades ago, when numerous clinical studies have concluded that prescription of L-type Ca 2+ channel blockers (CCBs) for hypertensive patients decreased arterial pressure, but produced stimulation of sympathetic hyperactivity. Indeed, initially these adverse effects of CCBs have been attributed to adjust reflex of arterial pressure, but this conclusion remained not completely satisfactory. The year of 2013 would change this history forever! Through an original experiment, we revealed that the "calcium paradox" phenomenon came from increased transmitter release from sympathetic neurons stimulated by CCBs due to its handling on the Ca 2+ /cAMP signalling interaction. Then, the manipulation of Ca 2+ /cAMP signalling interaction could improve therapeutic strategies for stimulating synaptic transmission compromised by transmitter release deficit, and attenuating death of neurons.
... For example: the association of Levodopa with CCBs or rolipram could dramatically improve typical antiparkinsonism medicines, mainly by reducing their adverse effects and increasing their effectiveness. This new pharmacological strategy could be alternatively used for treatment of the symptoms of neurodegenerative diseases [16][17][18][19][20][21][22][23]. ...
... 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 Ca 2+ /cAMP interaction, could greatly contribute to enhance therapeutic strategies for increasing neuroprotection [16][17][18][19][20][21][22][23]. Thus, the association of typical antiparkinsonism medicines with CCBs or rolipram could dramatically improve antiparkinsonism therapies, mainly by reducing adverse effects and improving effectiveness of these currently medicines [16][17][18][19][20][21][22][23]. ...
... Finally, novel strategies to treat Parkinson´s diseases, throughout our recent discovery entitled "calcium paradox" phenomenon due to Ca 2+ /cAMP interaction, could greatly contribute to enhance therapeutic strategies for increasing neuroprotection [16][17][18][19][20][21][22][23]. Thus, the association of typical antiparkinsonism medicines with CCBs or rolipram could dramatically improve antiparkinsonism therapies, mainly by reducing adverse effects and improving effectiveness of these currently medicines [16][17][18][19][20][21][22][23]. ...
The sympathetic hyperactivity, and tachycardia, are the main adverse effects reported since 70´s by hyperten-sive patients that use L-type Ca 2+ channel blockers (CCBs). Our discovery revealed that the sympathetic hyperactivity was resulting of increase of transmitter release from sympathetic neurons stimulated by CCBs due to its interference on the interaction between the intracellular signalling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP interaction). This discovery may produce new paths for the understanding of the cellular and molecular mechanisms involved in the pathogenesis of neurodegenerative diseases. In this way, novel journeys for the development of new pharmacological strategies more effective for the treatment of Parkinson´s may be initiated.
