Dexmedetomidine (DEX) is a highly selective α₂-adrenoceptor agonist with sedative effects on sleep homeostasis. Oxytocin-expressing (OXT) neurons in the paraventricular nucleus (PVN) of the hypothalamus (PVN^OXT) regulate sexual reproduction, drinking, sleep-wakefulness, and other instinctive behaviors. To investigate the effect of DEX on the activity and signal transmission of PVN^OXT in regulating the sleep-wakefulness cycle. Here, we employed OXT-cre mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in PVN^OXT neurons. Combining chemogenetic methods with electroencephalogram (EEG) /electromyogram (EMG) recordings, we found that cannula injection of DEX in PVN significantly increased the duration of non-rapid eye movement (NREM) sleep in mice. Furthermore, the chemogenetic activation of PVN^OXT neurons using i.p. injection of clozapine N-oxide (CNO) after cannula injection of DEX to PVN led to a substantial increase in wakefulness. Electrophysiological results showed that DEX decreased the frequency of action potential (AP) and the spontaneous excitatory postsynaptic current (sEPSC) of PVN^OXT neurons through α₂-adrenoceptors. Therefore, these results identify that DEX promotes sleep and maintains sleep homeostasis by inhibiting PVN^OXT neurons through the α₂-adrenoceptor.

01 Jun 2024·Pharmacology Biochemistry and Behavior

Limited bedding and nesting increases ethanol drinking in female rats

Article

Author: Salazar, P ; McGraw, M K ; Berquist, M D ; Brents, L K ; Gunnell, M ; Parks, B J ; Morrison, L ; Tobacyk, J

Prenatal opioid exposure (POE) and postnatal adverse experiences are early life adversities (ELA) that often co-occur and increase problematic alcohol (EtOH) drinking during adolescence. We investigated the relationship between POE, postnatal adversity, and adolescent EtOH drinking in rats. We also sought to determine whether ELAs affect alpha-adrenoceptor density in the brain because the noradrenergic system is involved in problematic alcohol drinking and its treatment. We hypothesized that the combination of POE and postnatal adversity will increase alcohol drinking in rats compared to rats with exposure to either adversity alone or to control. We also predicted that POE and postnatal adversity would increase α₁-adrenoceptor density and decrease α₂-adrenoceptor density in brain to confer a stress-responsive phenotype. Pregnant rats received morphine (15 mg/kg/day) or saline via subcutaneous minipumps from gestational day 9 until birth. Limited bedding and nesting (LBN) procedures were introduced from postnatal day (PD) 3-11 to mimic early life adversity-scarcity. Offspring rats (PD 31-33) were given opportunities to drink EtOH (20 %, v/v) using intermittent-access, two-bottle choice (with water) procedures. Rats given access to EtOH were assigned into sub-groups that were injected with either yohimbine (1 mg/kg, ip) or vehicle (2 % DMSO, ip) 30 min prior to each EtOH access session to determine the effects of α₂-adrenoceptor inhibition on alcohol drinking. We harvested cortices, brainstems, and hypothalami from EtOH-naïve littermates on either PD 30 or PD 70 and conducted radioligand receptor binding assays to quantify α₁- and α₂-adrenoceptor densities. Contrary to our hypothesis, only LBN alone increased EtOH intake in female adolescent rats compared to female rats with POE. Neither POE nor LBN affected α₁- or α₂-adrenoceptor densities in the cortex, brainstem, or hypothalamus of early- or late-aged adolescent rats. These results suggest a complex interaction between ELA type and sex on alcohol drinking.

01 May 2024·Biomedicine & Pharmacotherapy

Dexmedetomidine attenuates lipopolysaccharide-induced renal cell fibrotic phenotypic changes by inhibiting necroinflammation via activating α2-adrenoceptor: A combined randomised animal and in vitro study

Article

Author: Liu, Yi ; Zhao, Hailin ; Alam, Azeem ; Wu, Lingzhi ; Kamath, Priyanka ; Sun, Qizhe ; Sun, Yibing ; Chen, Qian ; Chang, Enqiang ; Ma, Daqing ; Liang, Min

BACKGROUNDAcute kidney injury (AKI) was reported to be one of the initiators of chronic kidney disease (CKD) development. Necroinflammation may contribute to the progression from AKI to CKD. Dexmedetomidine (Dex), a highly selective α₂-adrenoreceptor (AR) agonist, has cytoprotective and "anti-" inflammation effects. This study was designed to investigate the anti-fibrotic properties of Dex in sepsis models.METHODSC57BL/6 mice were randomly treated with an i.p. injection of lipopolysaccharides (LPS) (10 mg/kg) alone, LPS with Dex (25 μg/kg), or LPS, Dex and Atipamezole (Atip, an α₂-adrenoreceptor antagonist) (500 μg/kg) (n=5/group). Human proximal tubular epithelial cells (HK2) were also cultured and then exposed to LPS (1 μg/ml) alone, LPS and Dex (1 μM), transforming growth factor-beta 1 (TGF-β1) (5 ng/ml) alone, TGF-β1 and Dex, with or without Atip (100 μM) in culture media. Epithelial-mesenchymal transition (EMT), cell necrosis, necroptosis and pyroptosis, and c-Jun N-terminal kinase (JNK) phosphorylation were then determined.RESULTSDex treatment significantly alleviated LPS-induced AKI, myofibroblast activation, NLRP3 inflammasome activation, and necroptosis in mice. Atip counteracted its protective effects. Dex attenuated LPS or TGF-β1 induced EMT and also prevented necrosis, necroptosis, and pyroptosis in response to LPS stimulation in the HK2 cells. The anti-EMT effects of Dex were associated with JNK phosphorylation.CONCLUSIONSDex reduced EMT following LPS stimulation whilst simultaneously inhibiting pyroptosis and necroptosis via α₂-AR activation in the renal tubular cells. The "anti-fibrotic" and cytoprotective properties and its clinical use of Dex need to be further studied.

News (Medical) associated with Alpha 2 adrenoceptor

21 Nov 2022

·www.globenewswire.com

Ocuphire to Present at Five Upcoming Investor/Industry Conferences

FARMINGTON HILLS, Mich., Nov. 21, 2022 (GLOBE NEWSWIRE) -- Ocuphire Pharma, Inc. (Nasdaq: OCUP), a clinical-stage ophthalmic biopharmaceutical company focused on developing and commercializing therapies for the treatment of refractive and retinal eye disorders, today announced that Mina Sooch, MBA, founder and CEO will present at several investor conferences in November and December, including the BTIG Ophthalmology Day, Alliance Global Partners (AGP) Biotech Conference, Ophthalmology Innovation Summit (OIS XII), Cantor Dermatology, Ophthalmology & Medtech Conference, and the Planet MicroCap Conference, being held on the following dates: BTIG Ophthalmology Day – November 29, 2022 Title:Fireside Chat with Ocuphire Pharma (OCUP)Date:Tuesday, November 29, 2022 at 9:30am – 9:55am ETHost:Julian Harrison, MSPresenter:Mina Sooch, MBA, CEO and FounderFormat:Virtual, 1x1 meetings available Alliance Global Partners Biotech Conference – November 30, 2022 Title:Ocuphire Pharma (OCUP) 1x1 MeetingsDate:Wednesday, November 30, 2022Presenter:Ocuphire Management TeamFormat:Virtual, 1x1 meetings available OIS XII San Diego – December 2-3, 2022 Title:Ocuphire Pharma (OCUP) Company PresentationDate:Saturday, December 3, 2022, at 11:40am PTSession:Retina Innovation ShowcasePresenter:Mina Sooch, MBA, CEO and FounderLocation:Hard Rock Hotel, San Diego (in-person)Conf. Registration:Link Cantor Medical & Aesthetic Dermatology, Ophthalmology, & Medtech/Diagnostic Conference – December 8, 2022 Panel Title:Ophthalmology Panel, Ongoing & Upcoming Commercial Stories: Opportunities, Challenges, And Finding The Line Of Sight For SuccessDate:Thursday, December 8, 2022, at 3:45pm – 4:30pm ETHosts:Jennifer Kim and Kristen KluskaPresenter:Mina Sooch, MBA, CEO and FounderLocation:Fountainbleau Hotel in Miami, FL (in-person) Planet MicroCap Conference – December 6-8, 2022 Title:Ocuphire Pharma (OCUP) Company PresentationDate:Thursday, December 8, 2022, at 11:30 am – 12:00 pm ETParticipant:Mina Sooch, MBA, CEO and FounderFormat:Virtual, 1x1 meetings availableWebcast.:Link Virtual CEO Presentation will be on Planet MicroCap's YouTube channel If you are interested in arranging a 1x1 meeting at one of these events, please contact your conference representative or ir@ocuphire.com. For more details, see the Investor Events section of Ocuphire’s corporate website. About Ocuphire Pharma Ocuphire is a publicly traded (Nasdaq: OCUP), clinical-stage, ophthalmic biopharmaceutical company focused on developing and commercializing small-molecule therapies for the treatment of refractive and retinal eye disorders. The Company’s lead product candidate, Nyxol® eye drops (0.75% phentolamine ophthalmic solution), is a once-daily, preservative-free eye drop formulation of phentolamine mesylate, a non-selective alpha-1 and alpha-2 adrenergic antagonist designed to reduce pupil size and is being developed for three indications, including reversal of pharmacologically induced mydriasis (RM), presbyopia and dim light or night vision disturbances (NVD). Nyxol has been studied in 12 completed clinical trials, including recently reported positive data from the following trials: MIRA-2 (NCT04620213) and MIRA-3 (NCT05134974) Phase 3 registration trials, and MIRA-4 (NCT05223478) Phase 3 pediatric safety trial for the treatment of RM VEGA-1 (NCT04675151) Phase 2 trial of Nyxol for treatment of presbyopia, which evaluated both Nyxol as a single agent and Nyxol with low dose pilocarpine (“LDP”) 0.4% as adjunctive therapy LYNX-1 (NCT04638660) Phase 3 trial of Nyxol for night vision disturbances (NVD) Ocuphire’s second product candidate, APX3330, is an oral tablet designed to inhibit angiogenesis and inflammation pathways relevant to retinal and choroidal vascular diseases, such as diabetic retinopathy (DR) and diabetic macular edema (DME). APX3330 has been studied in 11 Phase 1 and 2 trials. The Company announced the completion of last patient last visit in late August in Phase 2b ZETA-1 (NCT04692688) trial. For more information, visit www.ocuphire.com. Contacts Corporate Investor Relations Mina Sooch, MBA CEO & Founder ir@ocuphire.com Corey Davis, Ph.D. LifeSci Advisors cdavis@lifesciadvisors.comBret Shapiro CoreIR brets@coreir.com

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