Imidazoline Receptor System: The Past, the Present, and the Future

Bousquet, Pascal; Hudson, Alan L.; Garcı́a-Sevilla, Jesús A.; Li, Jun-Xu

doi:10.1124/pr.118.016311

Cited by 80 publications

(80 citation statements)

References 299 publications

(391 reference statements)

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“…). The data set included structurally diverse bicyclic αiminophosphonates (Schemes 2 and 3) with a wide range of binding activity on I 2 -IR (pKi I 2 = 3.11-10.28) and α 2 -AR (pKi α2 = 3.38-10.27) ensuring the good quality and applicability of the 3D-QSAR models. Additionally, we added four I 2 -IR standard ligands (tracizoline 5, idazoxan 4,BU99008 2 and LSL60101 3), in both data sets to compare and validate our results.…”

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Bicyclic α-Iminophosphonates as High Affinity Imidazoline I₂ Receptor Ligands for Alzheimer’s Disease

et al. 2020

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Imidazoline I 2 receptors (I 2-IR), widely distributed in the CNS and altered in patients that suffered from neurodegenerative disorders, are orphan from the structural point of view and new I 2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and 3D-QSAR studies of a new family of bicyclic -iminophosphonates endowed with relevant affinities for human brain I 2-IR. Acute treatment in mice with a selected compound significantly decreased the FADD protein in the hippocampus, a key marker in neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer's disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer's disease. Therefore bicyclic -iminophosphonates are tools that may open new therapeutic avenues for I 2-IR, particularly for unmet neurodegenerative conditions.

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Bicyclic α-Iminophosphonates as High Affinity Imidazoline I₂ Receptor Ligands for Alzheimer’s Disease

et al. 2020

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“…I 2 imidazoline receptors were recognized by specific drugs, including idazoxan and are expressed mainly on the outer membrane of mitochondria in astrocytes (Regunathan, Feinstein, & Reis, 1993a; Regunathan, Meeley, & Reis, 1993b; Tesson, Prip‐Buus, Lemoine, Pegorier, & Parini, 1991). I 3 receptor, an atypical imidazoline subtype, was associated with the K ATP channel and is involved in insulin secretion (Bousquet et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer's disease

Mirzaei

Mota

Birch

et al. 2020

British J Pharmacology

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Background and Purpose: Activation of type 2 imidazoline receptors has been shown to exhibit neuroprotective properties including anti-apoptotic and anti-inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the imidazoline-2 ligand BU224 in a model of amyloidosis.Experimental Approach: Six-month-old female transgenic 5XFAD and wild-type (WT) mice were treated intraperitoneally with 5-mgÁkg −1 BU224 or vehicle twice a day for 10 days. Behavioural tests were performed for cognitive functions and neuropathological changes were investigated by immunohistochemistry, Western blot, ELISA and qPCR. Effects of BU224 on amyloid precursor protein (APP) processing, spine density and calcium imaging were analysed in brain organotypic cultures and N2a cells.Key Results: BU224 treatment attenuated spatial and perirhinal cortex-dependent recognition memory deficits in 5XFAD mice. Fear-conditioning testing revealed that BU224 also improved both associative learning and hippocampal-and amygdaladependent memory in transgenic but not in WT mice. In the brain, BU224 reduced levels of the microglial marker Iba1 and pro-inflammatory cytokines IL-1β and TNF-α and increased the expression of astrocytic marker GFAP in 5XFAD mice. These beneficial effects were not associated with changes in amyloid pathology, neuronal apoptosis, mitochondrial density, oxidative stress or autophagy markers. Interestingly, ex vivo and in vitro studies suggested that BU224 treatment increased the size of dendritic spines and induced a threefold reduction in amyloid-β (Aβ)-induced functional changes in NMDA receptors. Conclusion and Implications:Sub-chronic treatment with BU224 restores memory and reduces inflammation in transgenic AD mice, at stages when animals display severe pathology.

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“…Кроме того, в настоящее время большое внимание уделяется возможности замедления процессов старения сосудистой стенки на фоне применения АИР. Известно, что инсулинорезистентность может способствовать ускорению укорочения теломеров в стволовых клетках и преждевременному старению сосудов [32]. Вероятно, позитивное моделирование углеводного обмена при назначении моксонидина сопровождается и регрессом возрастных изменений в стенке сосуда.…”

Section: Discussionunclassified

Antihypertensive and Vasoprotective Effects of Combined Pharmacotherapy in Patients with Arterial Hypertension and Prediabetes

et al. 2020

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Aim To evaluate effects of different types of combination drug therapy on indexes of 24-h blood pressure monitoring (24-h BPM), arterial stiffness, and central aortic pressure (CAP) in patients with arterial hypertension (AH) and prediabetes.Materials and methods The study included 120 patients with AH and prediabetes. After randomization using envelopes, three treatment groups were formed: group 1, patients receiving perindopril, indapamide SR, and metformin (n=40); group 2, patients receiving perindopril, moxonidin, and metformin (n=40); and group 3, patients receiving perindopril, indapamide SR, and amlodipine (n=40). 24-h BPM, determination of arterial stiffness, and measurement of CAP were performed for all patients.Results After 24 weeks of treatment, patients of all groups showed statistically significant improvements of most indexes of 24-h BPM, arterial stiffness, and CAP. In groups 2 and 3, the treatment was associated with significantly more pronounced beneficial changes in 24-BPM, arterial stiffness, and CAP compared to group 1. Antihypertensive and vasoprotective effects of the perindopril+moxonidin+metformin and perindopril+indopamide SR+amlodipine combinations were comparable.Conclusion The observed statistically significant antihypertensive and vasoprotective effects of the perindopril+moxonidin+metformin combination along with its known positive metabolic effect allow recommendation of this combination therapy to patients with AH and prediabetes as an effective strategy for BP control.

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Imidazoline Receptor System: The Past, the Present, and the Future

Cited by 80 publications

References 299 publications

Bicyclic α-Iminophosphonates as High Affinity Imidazoline I₂ Receptor Ligands for Alzheimer’s Disease

Bicyclic α-Iminophosphonates as High Affinity Imidazoline I₂ Receptor Ligands for Alzheimer’s Disease

Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer's disease

Antihypertensive and Vasoprotective Effects of Combined Pharmacotherapy in Patients with Arterial Hypertension and Prediabetes

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Imidazoline Receptor System: The Past, the Present, and the Future

Cited by 80 publications

References 299 publications

Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer’s Disease

Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer’s Disease

Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer's disease

Antihypertensive and Vasoprotective Effects of Combined Pharmacotherapy in Patients with Arterial Hypertension and Prediabetes

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Bicyclic α-Iminophosphonates as High Affinity Imidazoline I₂ Receptor Ligands for Alzheimer’s Disease

Bicyclic α-Iminophosphonates as High Affinity Imidazoline I₂ Receptor Ligands for Alzheimer’s Disease