Multi-target novel neuroprotective compound ITH33/IQM9.21 inhibits calcium entry, calcium signals and exocytosis

Maroto, Marcos; Diego, Antonio M. G. de; Albiñana, E.; Fernández-Morales, José Carlos; Caricati‐Neto, Afonso; Jurkiewicz, Aron; Yáñez, Matilde; Rodríguez‐Franco, María Isabel; Conde, Santiago; Arce, Mariana P.; Hernández‐Guijo, Jesús M.; Garcı́a, Antonio G.

doi:10.1016/j.ceca.2011.06.006

Cited by 17 publications

(25 citation statements)

References 51 publications

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“…Therefore, the cumulative knowledge on the pathogenesis of AD 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].…”

Section: Current Therapy To Treat Alzheimer´s Disease (Ad)mentioning

confidence: 99%

“…Deleterious excess Ca 2+ influx is also another constituent seen in aging and neurodegenerative diseases [13]. Thus, 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].…”

Section: Current Therapy To Treat Alzheimer´s Disease (Ad)mentioning

confidence: 99%

“…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. Thus, the inhibition of acetylcholine degradation by AChE is a potential goal to treat AD [11,12]. Deleterious excess Ca 2+ influx is also another constituent seen in aging and neurodegenerative diseases [13].…”

Section: Current Therapy To Treat Alzheimer´s Disease (Ad)mentioning

confidence: 99%

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Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

Caricati‐Neto¹,

Bergantin²

2017

J Syst Integr Neurosci

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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 antihypertensive 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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Section: Current Therapy To Treat Alzheimer´s Disease (Ad)mentioning

confidence: 99%

Section: Current Therapy To Treat Alzheimer´s Disease (Ad)mentioning

confidence: 99%

Section: Current Therapy To Treat Alzheimer´s Disease (Ad)mentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

Caricati‐Neto¹,

Bergantin²

2017

J Syst Integr Neurosci

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“…76,77 Here we propose a similar approach, also using L-glutamic acid as a linker for the following bioactive moieties: (1) a DHP group (i.e., nimodipine-like) to target the L-type VDCCs, thus mitigating the excess Ca 2+ entry into the soma of vulnerable neurons; (2) a benzothiazepine group (i.e., CGP37157-like) to target the MNCX and abort the futile MCC in vulnerable neurons; and (3) a polyphenolic group (i.e., resveratrol-like) to combat excess free radical production in vulnerable neurons ( Figure 5). An aliphatic group linked with an ester bond could facilitate the crossing of the blood-brain barrier (BBB) of this multifunctional compound.…”

Section: ■ Multitarget Neuroprotective Compounds To Correct the Disrumentioning

confidence: 99%

“…76 Compound ITH33/IQM9.21 from this family reduces infarct volume in a photothrombotic model of permanent focal cerebral ischemia in mice (Silvia Lorrio, personal communication) and causes a gradual, slowdeveloping reversible blockade of VDCCs. 77 Multitarget compounds acting on NMDAR Ca 2+ channels have also been synthesized, inspired by carvedilol, a vasodilator beta-blocker having antioxidant and neuroprotective properties. 78 In this report, the tetrahydroacridine moiety from tacrine and the carbazole core from carvedilol were linked.…”

Section: Acs Chemical Neurosciencementioning

confidence: 99%

Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

Fernández‐Morales

Arranz-Tagarro

Calvo-Gallardo³

et al. 2012

ACS Chem. Neurosci.

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For the last two decades, most efforts on new drug development to treat Alzheimer's disease have been focused to inhibit the synthesis of amyloid beta (Aβ), to prevent Aβ deposition, or to clear up Aβ plaques from the brain of Alzheimer's disease (AD) patients. Other pathogenic mechanisms such as the hyperphosphorylation of the microtubular tau protein (that forms neurofibrillary tangles) have also been addressed as, for instance, with inhibitors of the enzyme glycogen synthase-3 kinase beta (GSK3β). However, in spite of their proven efficacy in animal models of AD, all these compounds have so far failed in clinical trials done in AD patients. It seems therefore desirable to explore new concepts and strategies in the field of drug development for AD. We analyze here our hypothesis that a trifunctional chemical entity acting on the L subtype of voltage-dependent Ca 2+ channels (VDCCs) and on the mitochondrial Na + /Ca 2+ exchanger (MNCX), and having additional antioxidant properties, may efficiently delay or stop the death of vulnerable neurons in the brain of AD patients. In recent years, evidence has accumulated indicating that enhanced neuronal Ca 2+ cycling (NCC) and futile mitochondrial Ca 2+ cycling (MCC) are central stage in activating calpain and calcineurin, as well as the intrinsic mitochondrial pathway for apoptosis, leading to death of vulnerable neurons. An additional contributing factor to neuronal death is the excess free radical production linked to distortion of Ca 2+ homeostasis. We propose that an hybrid compound containing a dihydropyridine moiety (to block L channels and mitigate Ca 2+ entry) and a benzothiazepine moiety (to block the MNCX and slow down the rate of Ca 2+ efflux from the mitochondrial matrix into the cytosol), as well as a polyphenol moiety (to sequester excess free radicals) could break down the pathological enhanced NCC and MCC, thus delaying the initiation of apoptosis and the death of vulnerable neurons. In so doing, such a trifunctional compound could eventually become a neuroprotective medicine capable of delaying disease progression in AD patients.

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Multitarget Drugs for Stabilization of Calcium Cycling and Neuroprotection in Neurodegenerative Diseases and Stroke

Diego

Lorrio

Hernández‐Guijo

et al. 2012

Therapeutic Targets

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Multi-target novel neuroprotective compound ITH33/IQM9.21 inhibits calcium entry, calcium signals and exocytosis

Cited by 17 publications

References 51 publications

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

Multitarget Drugs for Stabilization of Calcium Cycling and Neuroprotection in Neurodegenerative Diseases and Stroke

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