Activation of the sigma-1 receptor attenuates blood–brain barrier disruption by inhibiting amyloid deposition in Alzheimer’s disease mice

An, Yang; Qi, Yue; Liu, Ying; Zhao, Li; Yang, Caiyu; Dong, Jinqiao

doi:10.1016/j.neulet.2022.136528

Cited by 10 publications

(6 citation statements)

References 21 publications

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“…It also indicated an involvement of the decreased Sig-1r function in the neuropathology of AD, which is consistent with previous studies, demonstrating a large decrease and loss of Sig-1r in brain regions of individuals in early stage of AD [ 5 , 51 ]. In other studies, it was found that another Sig-1r agonist, PRE084, improved mitochondrial respiratory impairment and alleviated blood-brain barrier disruption in the Aβ-injected animals [ 14 , 52 ]. Both PRE084 and DMT significantly reduced Aβ-induced neuroinflammatio n[ 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Sig-1r is widely expressed throughout the central nervous system, with a high density in brain regions associated with learning and memory, such as the hippocampus and cortex [ 11 – 13 ]. Sig-1r activation inhibited Aβ deposition [ 14 ], whereas Sig-1r deactivation resulted in the development of AD [ 14 , 15 ]. Several Sig-1r agonists are suggested to have benefits in alleviating neurodegenerative diseases in cultured cells and animal models [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer’s disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk

Cheng,

Lei,

Chu

et al. 2024

Alz Res Therapy

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Background Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer’s disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay. Methods 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aβ accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated. Results chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aβ accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD. Conclusion The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer’s disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk

Cheng,

Lei,

Chu

et al. 2024

Alz Res Therapy

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“…We have demonstrated the increase in BBB permeability by cocaine by direct visualization with miniaturized fluorescence microscopy [28]. However, chronic administration of the Sigma-1R agonist, PRE-084, attenuated BBB dysfunction in mouse models of vascular dementia [22] and Alzheimer's disease [29].…”

Section: Introductionmentioning

confidence: 94%

Modulation of the Blood–Brain Barrier by Sigma-1R Activation

Brailoiu,

Barr,

Wittorf

et al. 2024

IJMS

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Sigma non-opioid intracellular receptor 1 (Sigma-1R) is an intracellular chaperone protein residing on the endoplasmic reticulum at the mitochondrial-associated membrane (MAM) region. Sigma-1R is abundant in the brain and is involved in several physiological processes as well as in various disease states. The role of Sigma-1R at the blood–brain barrier (BBB) is incompletely characterized. In this study, the effect of Sigma-1R activation was investigated in vitro on rat brain microvascular endothelial cells (RBMVEC), an important component of the blood–brain barrier (BBB), and in vivo on BBB permeability in rats. The Sigma-1R agonist PRE-084 produced a dose-dependent increase in mitochondrial calcium, and mitochondrial and cytosolic reactive oxygen species (ROS) in RBMVEC. PRE-084 decreased the electrical resistance of the RBMVEC monolayer, measured with the electric cell-substrate impedance sensing (ECIS) method, indicating barrier disruption. These effects were reduced by pretreatment with Sigma-1R antagonists, BD 1047 and NE 100. In vivo assessment of BBB permeability in rats indicates that PRE-084 produced a dose-dependent increase in brain extravasation of Evans Blue and sodium fluorescein brain; the effect was reduced by the Sigma-1R antagonists. Immunocytochemistry studies indicate that PRE-084 produced a disruption of tight and adherens junctions and actin cytoskeleton. The brain microcirculation was directly visualized in vivo in the prefrontal cortex of awake rats with a miniature integrated fluorescence microscope (aka, miniscope; Doric Lenses Inc.). Miniscope studies indicate that PRE-084 increased sodium fluorescein extravasation in vivo. Taken together, these results indicate that Sigma-1R activation promoted oxidative stress and increased BBB permeability.

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“…Pre-clinical data have shown that PRE-084 can attenuate the blood–brain barrier (BBB) disruption caused by Aβ. The study showed that PRE-084 protected the integrity of the BBB by preventing the deposition of Aβ (insoluble) Aβ 1–40 and Aβ 1–42 levels in the brains of mice, and increasing vascular endothelial growth factor (VEGF) and ApoE receptor [ 386 ]. PRE-084 also increases the expression of glial cell line-derived neurotrophic factor (GDNF) [ 387 ] and BDNF [ 388 ].…”

Section: Sigma Receptor Ligands For Neurological Diseasementioning

confidence: 99%

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

Malar,

Thitilertdecha,

Ruckvongacheep

et al. 2023

CNS Drugs

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The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.

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Activation of the sigma-1 receptor attenuates blood–brain barrier disruption by inhibiting amyloid deposition in Alzheimer’s disease mice

Cited by 10 publications

References 21 publications

N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer’s disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk

N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer’s disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk

Modulation of the Blood–Brain Barrier by Sigma-1R Activation

Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

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