New Perspectives for Developing Therapeutic Bioconjugates of Metabolite-Depleting Enzymes: Lessons Learned Combating Glutamate Excitotoxicity

Zaghmi, Ahlem; Pérez‐Mato, María; Dopico-López, Antonio; Candamo-Lourido, María; Campos, Francisco; Gauthier, Marc A.

doi:10.1021/acs.biomac.2c00117

Cited by 5 publications

(5 citation statements)

References 81 publications

(148 reference statements)

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“…Hypoxemia mediates oxidative stress in the brain, which is associated with the occurrence of migraine and epilepsy 57 . Several lines of evidence suggest that the immediate precipitant of seizure or headache attack is an acute rise in brain oxidative stress caused by nearly all provoked factors 58 . For example, stimuli including noise, sleep deprivation, and psychosocial stress can generate ROS, which threaten neuronal viability and elicit migraine or epilepsy 59 .…”

Section: Discussionmentioning

confidence: 99%

“… 57 Several lines of evidence suggest that the immediate precipitant of seizure or headache attack is an acute rise in brain oxidative stress caused by nearly all provoked factors. 58 For example, stimuli including noise, sleep deprivation, and psychosocial stress can generate ROS, which threaten neuronal viability and elicit migraine or epilepsy. 59 ROS also play an important role in the development of refractory epilepsy, which likely occurs through the upregulation of P‐glycoprotein.…”

Section: Discussionmentioning

confidence: 99%

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Multisite and multitimepoint proteomics reveal that patent foramen ovale closure improves migraine and epilepsy by reducing right‐to‐left shunt‐induced hypoxia

Dong,

Lu,

et al. 2023

MedComm

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Patent foramen ovale (PFO) is a congenital defect in the partition between two atria, which may cause right‐to‐left shunt (RLS), leading to neurological chronic diseases with episodic manifestations (NCDEMs), such as migraine and epilepsy. However, whether PFO closure was effective in improving NCDEMs and the mechanism were unclear. Twenty‐eight patients with migraine or epilepsy who underwent PFO closure were recruited. Notably, approximately half of patients received 50% or more reduction in seizure or headache attacks. Meanwhile, the postoperative blood oxygen partial pressure and oxygen saturation were elevated after PFO closure. Multisite (peripheral, right, and left atrial) and multitimepoint (before and after surgery) plasma proteomics from patients showed that the levels of free hemoglobin and cell adhesion molecules (CAMs) were significantly increased after PFO closure, which may be related to the relief of the hypoxic state. Furtherly, the omics data from multiple brain regions of mice revealed that a large number of proteins were differentially expressed in the occipital region in response to PFO, including redox molecules and CAMs, suggesting PFO‐caused hypoxia may have great impacts on occipital region. Collectively, PFO may cause NCDEMs due to RLS‐induced hypoxia, and PFO closure could prevent RLS to improve migraine and epilepsy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multisite and multitimepoint proteomics reveal that patent foramen ovale closure improves migraine and epilepsy by reducing right‐to‐left shunt‐induced hypoxia

Dong,

Lu,

et al. 2023

MedComm

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“…Glutamate is the primary excitatory neurotransmitter and contributes to synaptic plasticity, cognitive activities, and motivational and emotional behavior in the brain. 33 Multiple evidence suggests that depression is associated with the glutamate system. 34,35 Researchers have found elevated levels of glutamate in the blood, cerebrospinal fluid (CSF), and brains of patients with depression, 36,37 as well as N-methyl-D-aspartate receptor (NMDAR) subunit disturbances in the brain.…”

Section: Neurotransmitter Systemsmentioning

confidence: 99%

“…Glutamate is the primary excitatory neurotransmitter and contributes to synaptic plasticity, cognitive activities, and motivational and emotional behavior in the brain 33 . Multiple evidence suggests that depression is associated with the glutamate system 34,35 .…”

Section: Pathological Mechanisms Of Depressionmentioning

confidence: 99%

The molecular pathophysiology of depression and the new therapeutics

Tian

et al. 2022

MedComm

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Major depressive disorder (MDD) is a highly prevalent and disabling disorder. Despite the many hypotheses proposed to understand the molecular pathophysiology of depression, it is still unclear. Current treatments for depression are inadequate for many individuals, because of limited effectiveness, delayed efficacy (usually two weeks), and side effects. Consequently, novel drugs with increased speed of action and effectiveness are required. Ketamine has shown to have rapid, reliable, and long‐lasting antidepressant effects in treatment‐resistant MDD patients and represent a breakthrough therapy for patients with MDD; however, concerns regarding its efficacy, potential misuse, and side effects remain. In this review, we aimed to summarize molecular mechanisms and pharmacological treatments for depression. We focused on the fast antidepressant treatment and clarified the safety, tolerability, and efficacy of ketamine and its metabolites for the MDD treatment, along with a review of the potential pharmacological mechanisms, research challenges, and future clinical prospects.

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“…In addition, there is a natural mechanism in the CNS that scavenges glutamate through endothelial regulation between the brain and blood, and the accumulated glutamate can be driven by gradients to transfer to the blood through the cerebral vascular endothelial transporters [ 184 ]. Recently, an emerging protection strategy that reducing the concentration of glutamate in the blood to increase the driving force of glutamate efflux in the brain can ameliorate the harmful effects of glutamate after ischemia has been put forward, and it is effectively validated in a randomized, double-blind phase IIb clinical trial of 50 stroke patients [ 48 , 185 ]. Considering that, glutamate capture based on blood circulation may be a promising method for the treatment of acute ischemic stroke.…”

Section: Glutamate Uptake and Metabolic Inhibition Aggravating Synapt...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 Perspectives for Developing Therapeutic Bioconjugates of Metabolite-Depleting Enzymes: Lessons Learned Combating Glutamate Excitotoxicity

Cited by 5 publications

References 81 publications

Multisite and multitimepoint proteomics reveal that patent foramen ovale closure improves migraine and epilepsy by reducing right‐to‐left shunt‐induced hypoxia

Multisite and multitimepoint proteomics reveal that patent foramen ovale closure improves migraine and epilepsy by reducing right‐to‐left shunt‐induced hypoxia

The molecular pathophysiology of depression and the new therapeutics

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

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