![Increase of neurotransmission produced by pharmacological modulation of neural Ca 2+ /cAMP signaling interaction (A) Records showing that contractile responses mediated by neurotransmitter released from sympathetic nerves by means Electrical Field Stimulation (EFS) in rat vas deferens (neurogenic contractions) were significantly reduced by L-type CCB (verapamil) in high concentrations (> 10-6 M), but paradoxically increased in concentrations below 10-6 M, characterizing CCB-induced sympathetic hyperactivity. This increase of neurogenic contractions by verapamil (< 10-6 M) was potentiated by pre-treatment of isolated tissue with cAMP-enhancer compounds, such as rolipram 10-7 M; (B) IBMX 10-6 M; (C) and forskolin 10-7 M; (D) 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. [5].](https://www.researchgate.net/profile/Leandro-Bergantin/publication/325497996/figure/fig1/AS:632699479916544@1527858719375/Increase-of-neurotransmission-produced-by-pharmacological-modulation-of-neural-Ca-2_Q320.jpg)
![Increase of neurotransmitter release and attenuation of neuronal death (neuroprotection) produced by pharmacological modulation of the Ca 2+ /cAMP signaling interaction by combined use of L-type Ca 2+ Channel Blockers (CCB) and cAMP-enhancer compounds. PDE-phosphodiesterase inhibitors. Figure extracted from Bergantin and Caricati-Neto [5-14].](https://www.researchgate.net/profile/Leandro-Bergantin/publication/325497996/figure/fig2/AS:632699479945217@1527858719430/Increase-of-neurotransmitter-release-and-attenuation-of-neuronal-death-neuroprotection_Q320.jpg)
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New Therapeutic Strategy for the Neurodegenerative Diseases: Pharmacological Modulation of Ca2+ /Camp Signaling Interaction
Abstract and Figures
Due to the involvement of the imbalance of neuronal Ca2+ homeostasis in the pathogenesis of several neurodegener-ative diseases, the use of drugs to prevent or attenuate this imbalance emerged as a new therapeutic strategy for treating these diseases. Thus, our discovery of the involvement of the interaction between intracellular signaling pathways mediated by Ca2+ and cAMP (Ca2+ /cAMP signaling interaction) in the neurotransmission and neuroprotection, and its pharmacological modulation, could importantly contribute to the therapy of the neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's (PD) Diseases. Then, in this review we discussed the fundamental findings of the Ca2+ /cAMP signaling interaction, including its role in neuro-transmission and neuroprotection, and its potential role as a new therapeutic target for the treatment of the neurode-generative diseases.
Keywords Neurodegenerative diseases, Ca2+ /cAMP signaling interaction
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The pharmacological manipulation of interaction of the intracellular signalling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP interaction) may provide new insights for the pharmacotherapy of psychiatric disorders, dramatically impacting clinical pharmacology and translational medicine. Disorders mainly resulting by reduction of serotonin and catecholamine release in central nervous system could be directly impacted by the manipulation of the Ca 2+ /cAMP interaction, such as depression. Since 1975, several clinical studies have reported that administration of L-type Ca 2+ channel blockers (CCBs) produces reduction in vascular resistance and arterial pressure in hypertensive patients, associated with an increase in plasma noradrenaline levels and tachycardia characterized by sympathetic hyperactivity. During almost four decades these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical sympathetic hyperactivity produced by CCBs is due to its interference on the Ca 2+ / cAMP interaction. Then, the pharmacological manipulation of this interaction could be a more efficient therapeutic strategy for increasing serotoninergic and monoaminergic neurotransmission in depression.
Our discovery of the involvement of the interaction between intracellular signalling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP signaling interaction) in the neurotransmission and neuroprotection has produced important advances in the understanding of the pathophysiology and pharmacology of neurological and psychiatric disorders, such as Alzheimer´s and Parkinson's diseases. Interestingly, this discovery initiated decades ago when numerous clinical studies have reported that L-type Ca channel blockers (CCBs) used in antihypertensive pharmacotherapy 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 named "calcium paradox" remained unclear. In 2013, we discovered that these "calcium paradox" results of transmitter release from sympathetic neurons and adrenal chromaffin cells stimulated by CCBs due to its modulatory action on the Ca2+/cAMP signaling interaction. In addition, we discovered that this modulatory action attenuates neuronal death triggered by cytosolic Ca2+ overload. These findings open a large avenue 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.
Our discovery of the " calcium paradox " phenomenon due to interaction between Ca 2+ /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 Ca 2+ 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 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 is due to interaction of the Ca 2+ /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 Ca 2+ /cAMP interaction could be a more efficient therapeutic strategy for increasing neuroprotection and dopamine neurotransmitter release in Parkinson's disease.
Our discovery of " calcium paradox " phenomenon due to interaction of Ca 2+ /cAMP intracellular signalling pathways (Ca 2+ / cAMP interaction) may provide new insights for the treatment of psychiatric disorders, such as depression. This disorder is mainly resulting by reduction of serotonin and catecholamine release in central nervous system. Since 1975, several clinical studies have reported that administration of L-type Ca 2+ channel blockers (CCBs) produces reduction in vascular resistance and arterial pressure in hypertensive patients, associated with an increase in plasma noradrenaline levels and tachycardia characterized by sympathetic hyperactivity. During almost four decades, these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical sympathetic hyperactivity produced by CCBs is mediated by Ca 2+ /cAMP interaction. Then, the pharmacological manipulation of this interaction could be a more efficient therapeutic strategy for increasing serotoninergic and monoaminergic neurotransmission in depression.
Calcium channel blockers (CCBs) are widely used for reducing blood pressure of hypertensive patients. Recent reports document the beneficial effects of CCB for preventing dementia; however, the results are controversial. We aim to evaluate the risk of developing dementia among elderly hypertensive patients treated with CCB.
We designed a retrospective population-based cohort study using the records of the National Health Insurance Research Database of Taiwan dated from 2000 to 2010. The study cohort comprised 82,107 hypertensive patients of more than 60 years of age, and 4004 propensity score (PS)-matched pairs were selected according to age, sex, year of hypertension diagnosis, and baseline comorbidities. We employed a robust Cox proportional hazard model to estimate the hazard ratio (HR) of developing dementia in the PS-matched cohort.
The annual incidence of dementia in the CCB-exposure group was significantly lower than that in the comparator group (3.9 vs 6.9 per 1000 person-years, P < 0.01) during the follow-up period (4.4 ± 2.5 years). Based on the PS-matched cohort, the adjusted HR of dementia in the CCB-exposure group was significantly lower than that in comparator group (HR = 0.53, 95% confidence interval: 0.39–0.72, P < 0.01). Sensitivity and subgroup analyses also confirmed similar findings.
Our results provided evidence for an association between CCB use and a lower risk of developing dementia among the elderly hypertensive patients. Further studies are required to explore the causal relationship between CCB use and dementia.
Proglucagon-derived peptides, especially glucagon-like peptide-1 (GLP-1) and its long-acting mimetics, have exhibited neuroprotective effects in animal models of stroke. Several of these peptides are in clinical trials for stroke. Oxyntomodulin (OXM) is a proglucagon-derived peptide that co-activates the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR). The neuroprotective action of OXM, however, has not been thoroughly investigated. In this study, the neuroprotective effect of OXM was first examined in human neuroblastoma (SH-SY5Y) cells and rat primary cortical neurons. GLP-1R and GCGR antagonists, and inhibitors of various signaling pathways were used in cell culture to characterize the mechanisms of action of OXM. To evaluate translation in vivo, OXM-mediated neuroprotection was assessed in a 60-min, transient middle cerebral artery occlusion (MCAo) rat model of stroke. We found that OXM dose- and time-dependently increased cell viability and protected cells from glutamate toxicity and oxidative stress. These neuroprotective actions of OXM were mainly mediated through the GLP-1R. OXM induced intracellular cAMP production and activated cAMP-response element-binding protein (CREB). Furthermore, inhibition of the PKA and MAPK pathways, but not inhibition of the PI3K pathway, significantly attenuated the OXM neuroprotective actions. Intracerebroventricular administration of OXM significantly reduced cerebral infarct size and improved locomotor activities in MCAo stroke rats. Therefore, we conclude that OXM is neuroprotective against ischemic brain injury. The mechanisms of action involve induction of intracellular cAMP, activation of PKA and MAPK pathways and phosphorylation of CREB.
Parkinson's disease is a disabling hypokinetic neurological movement disorder in which the aetiology is unknown in the majority of cases. Current pharmacological treatments, though effective at restoring movement, are only symptomatic and do nothing to slow disease progression. Electrophysiological, epidemiological and neuropathological studies have implicated CaV1.3 subtype calcium channels in the pathogenesis of the disorder, and drugs with some selectivity for this ion channel (brain-penetrant dihydropyridine calcium channel blockers) are neuroprotective in animal models of the disease. Dihydropyridines have been safely used for decades to treat hypertension and other cardiovascular disorders. A phase II clinical trial found that isradipine was safely tolerated by patients with Parkinson's disease, and a phase III trial is currently underway to determine whether treatment with isradipine is neuroprotective and therefore able to slow the progression of Parkinson's disease. This manuscript reviews the current information about the use of dihydropyridines as therapy for Parkinson's disease and discusses the possible mechanism of action of these drugs, highlighting CaV1.3 calcium channels as a potential therapeutic target for neuroprotection in Parkinson's disease.
1) From discovery by Bergantin et al. (Cell Calcium, 2013) of involvement of interaction of intracellular signaling pathways mediated by Ca2+ and cAMP (Ca2+/cAMP interaction) in the paradoxical sympathetic hyperactivity produced by L-type CCB during antihypertensive therapy (phenomenon entitled as “calcium paradox”); 2) Physiological and pathological role of Ca2+/cAMP interaction on the secretory response of sympathetic neurons and adrenal chromaffin cells; 3) Potential pharmacological therapeutic translation to human health and disease of the “calcium paradox”: hypertension, neurological/psychiatric disorders (Alzheimer´s and Parkinson´s diseases, and depression) and drug interaction in practical medicine.
Neurodegeneration in Parkinson's disease starts years before a clinical diagnosis can be reliably made. The prediagnostic phase of the disease offers a window of opportunity in which disease-modifying therapies—ie, those aimed at delaying or preventing the progression to overt disease and its many complications—could be most beneficial, but no such therapies are available at present. The unravelling of 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. Advances in the understanding of this prediagnostic phase of Parkinson's disease (for which the clinical diagnostic and prognostic markers used in more advanced disease stages are not applicable) will lead to the identification of biomarkers of neurodegeneration and its progression. These biomarkers will, in turn, help to identify the optimum population to be included and the most appropriate outcomes to be assessed in trials of disease-modifying drugs. Potential risks to minimally symptomatic participants, some of whom might not progress to manifest Parkinson's disease, and individuals who do not wish to know their mutation carrier status, could pose specific ethical dilemmas in the design of these trials.