New Insights into the Structure–Activity Relationship and Neuroprotective Profile of Benzodiazepinone Derivatives of Neurounina-1 as Modulators of the Na+/Ca2+ Exchanger Isoforms

Magli, Elisa; Fattorusso, Caterina; Persico, Marco; Corvino, Angela; Esposito, Gianluca; Fiorino, Ferdinando; Luciano, Paolo; Perissutti, Elisa; Santagada, Vincenzo; Severino, Beatrice; Tedeschi, Valentina; Pannaccione, Anna; Pignataro, Giuseppe; Caliendo, Giuseppe; Annunziato, Lucio; Secondo, Agnese; Frecentese, Francesco

doi:10.1021/acs.jmedchem.1c01212

Cited by 9 publications

(8 citation statements)

References 64 publications

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“…The upregulation of SLN and CASQ expression in STIM1 +/D84G muscle provides adaptation to the augmented expression of SOCE by enhancing Ca 2+ storage and limiting SERCA1 refilling. In contrast, our studies show that cytosolic transfer of Ca 2+ into the nucleus by the NPC was reduced when D84G STIM1 was expressed in myoblasts ( 39 , 40 ). The consequence of lower [Ca 2+ ] N in STIM1 +/D84G myoblasts was likely due to altered mechanical properties of the nucleus.…”

Section: Discussioncontrasting

confidence: 85%

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice

Bryson,

Wang,

Zhou

et al. 2024

Journal of Clinical Investigation

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Stromal interaction molecule 1 (STIM1) is a Ca 2+ sensor located in the sarcoplasmic reticulum (SR) of skeletal muscle, where it is best known for its role in store-operated Ca 2+ entry (SOCE). Genetic syndromes resulting from STIM1 mutations are recognized as a cause of muscle weakness and atrophy. Here, we focused on a gain-of-function mutation that occurs in humans and mice (STIM1 +/D84G mice), in which muscles exhibited constitutive SOCE. Unexpectedly, this constitutive SOCE did not affect global Ca 2+ transients, SR Ca 2+ content, or excitation-contraction coupling (ECC) and was therefore unlikely to underlie the reduced muscle mass and weakness observed in these mice. Instead, we demonstrate that the presence of D84G STIM1 in the nuclear envelope of STIM1 +/D84G muscle disrupted nuclear-cytosolic coupling, causing severe derangement in nuclear architecture, DNA damage, and altered lamina A–associated gene expression. Functionally, we found that D84G STIM1 reduced the transfer of Ca 2+ from the cytosol to the nucleus in myoblasts, resulting in a reduction of [Ca 2+ ] N . Taken together, we propose a novel role for STIM1 in the nuclear envelope that links Ca 2+ signaling to nuclear stability in skeletal muscle.

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Section: Discussioncontrasting

confidence: 85%

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice

Bryson,

Wang,

Zhou

et al. 2024

Journal of Clinical Investigation

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“…as well as protected from OGD/R-and chemical hypoxia-induced primary cortical neurons damage in a dosedependent manner. 96…”

Section: Acid-sensing Ion Channels (Asics) Inhibitorsmentioning

confidence: 99%

“…Furthermore, 20 reduced infarct volume in a dose‐dependently with a wide therapeutic window (3 ~ 5 h after stroke) in tMCAO mice. Based on 20 , Magli and colleagues synthesized 21 (Figure 3), which displayed NCX1 and NCX3 agonistic activity (EC 50 = 3.5 nM for NCX1 and EC 50 = 2 μM for NCX3) as well as protected from OGD/R‐ and chemical hypoxia‐induced primary cortical neurons damage in a dose‐dependent manner 96 …”

Section: The Drugs/agents For the Treatment Of Ismentioning

confidence: 99%

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

Jia,

Jiao,

Wang

et al. 2023

Medicinal Research Reviews

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Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long‐term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti‐IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti‐IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti‐IS drugs/agents are briefly provided to move the field forward.

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“…Moreover, the different effects of various NCX subtypes can often occur. The activator targeted NCX1 and NCX3 has been demonstrated to display neuroprotection in preclinical models of cerebral ischemia via upregulation of the PI3K-Akt signaling pathway [ 69 , 70 ]. Thus, more studies are necessary to explore the therapeutic targeting of NCX based on the subtype specific in ischemic stroke.…”

Section: Excessive Synaptic or Extra-synaptic Glutamate Release Resul...mentioning

confidence: 99%

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Fan

Xie

Xing

et al. 2022

IJMS

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Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).

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New Insights into the Structure–Activity Relationship and Neuroprotective Profile of Benzodiazepinone Derivatives of Neurounina-1 as Modulators of the Na⁺/Ca²⁺ Exchanger Isoforms

Cited by 9 publications

References 64 publications

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice

The D84G mutation in STIM1 causes nuclear envelope dysfunction and myopathy in mice

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

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