Barnett S, Dong R, Briggs L, Moushey A, Li A (2020) Exaggerated postnatal surge of orexin and the effects of elimination of excess orexin on blood pressure in spontaneously hypertensive rats in postnatal development. bioRxiv 2020.06.17.158279. doi: 10.1101/2020.06.17.158279

Related Products: Orexin-B-SAP (Cat. #IT-20)

Cui S-Y, Huang Y-L, Cui X-Y, Zhao H-L, Hu X, Liu Y-T, Qin Y, Kurban N, Zhang Y-H (2020) A common neuronal mechanism of hypertension and sleep disturbances in spontaneously hypertensive rats: Role of orexinergic neurons. Prog Neuropsychopharmacol Biol Psychiatry 100:109902. doi: 10.1016/j.pnpbp.2020.109902

Objective: To investigate dynamic changes in sleep patterns during the development of hypertension.

Summary: Although the correlation between sleep disturbances and hypertension is very complex, common mechanisms may underlie these comorbidities.

Usage: Orexin-B-SAP (HCRT2-SAP) was administered in two injections/side (100 and 200 ng/0.5 μl/injection).

Related Products: Orexin-B-SAP (Cat. #IT-20)

Hasegawa H, Selway R, Gnoni V, Beniczky S, Williams SCR, Kryger M, Ferini-Strambi L, Goadsby P, Leschziner GD, Ashkan K, Rosenzweig I (2020) The subcortical belly of sleep: New possibilities in neuromodulation of basal ganglia?. Sleep Med Rev 52:101317. doi: 10.1016/j.smrv.2020.101317

Summary: Complete BF lesion with OX-SAP leads to coma-like state and flat EEG, reduced Fos in cerebral cortex (but high Fos in brainstem, thalamus, hypothalamus) selective (cholinergic or non-cholinergic) lesion does not have this effect.

Usage: Lesions of the basal forebrain were done by injecting a 0.1% solution of Orexin-SAP at four different sites.

See: Fuller P et al. Reassessment of the structural basis of the ascending arousal system. J Comp Neurol 519(5):933-956, 2011.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Bhyrapuneni G, Benade V, Daripelli S, Kamuju V, Shinde A, Abraham R, Nirogi R, Jasti V (2019) SUVN-G3031, histamine H3 receptor inverse agonist preclinical evaluation for the treatment of excessive daytime sleepiness in narcolepsy. Neuroscience 2019 Abstracts 502.07. Society for Neuroscience, Chicago, IL.

Summary: Numerous studies have demonstrated that brain histamine plays a crucial role in maintenance of wakefulness, attention, learning and other cognitive processes. SUVN-G3031, a potent histamine H3 receptor inverse agonist is being developed for the treatment of narcolepsy and other sleep related disorders. SUVN-G3031 is one of the lead molecules with hKi of 8.7 nM and has more than 100 fold selectivity against the related GPCRs. SUVN-G3031 exhibited desired pharmacokinetic properties and brain penetration. SUVN-G3031 blocked R-α-methylhistamine induced water intake and increased tele-methylhistamine levels in brain and cerebrospinal fluid. In the present study, SUVN-G3031 was evaluated in brain microdialysis and rodent models of electroencephalography (EEG). SUVN-G3031 was evaluated in brain microdialysis for evaluation of neurotransmitters like acetylcholine, histamine, dopamine and norepinephrine in male Wistar rats. EEG was used to evaluate the effects on sleep/ wake profile in rats and mice.A single oral administration of SUVN-G3031 produced significant increase in acetylcholine, histamine, dopamine and norepinephrine levels in the cortex. SUVN-G3031 produced no change in the dopamine levels of striatum and nucleus accumbens indicating that SUVN-G3031 may not have addiction liabilities. Narcoleptic-like sleep behavior was observed in rats injected with hypocretin-2-saporin in lateral hypothalamus. SUVN-G3031 produced significant increase in wakefulness with concomitant decrease in rapid eye movement (REM) sleep in these animals. These results are in agreement with EEG studies carried out in healthy male Wistar rats. Results from current studies provide strong evidence for the potential of SUVN-G3031 in the treatment of excessive daytime sleepiness associated with narcolepsy. First in human, Phase 1 studies for SUVN-G3031 are completed under US IND and SUVN-G3031 has shown desirable pharmacokinetic profile with safety and tolerability in healthy human volunteers. Phase 2 study for the treatment of excessive daytime sleepiness associated with narcolepsy is currently ongoing in USA.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Murillo-Rodríguez E, Millán-Aldaco D, Palomero-Rivero M, Morales-Lara D, Mechoulam R, Drucker-Colín R (2019) Cannabidiol partially blocks the excessive sleepiness in hypocretindeficient rats: Preliminary data. CNS Neurol Disord Drug Targets 18(9):705-712. doi: 10.2174/1871527318666191021143300

Objective: To determine whether the systemic injection of CBD (5 mg/kg, i.p.) would block the excessive sleepiness in a narcoleptic model.

Summary: Preliminary findings suggest that CBD might prevent sleepiness in narcolepsy.

Usage: Orexin-SAP (490 ng/0.5 μL, n= 10) was bilaterally injected into the LH of rats to eliminate HCRT leading to the establishment of narcoleptic-like behavior.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Benade V, Daripelli S, Tirumalasetty C, Subramanian R, Petlu S, Badange R, Nirogi R (2019) 0054 SUVN-G3031, a histamine H3 receptor inverse agonist produces wake promoting effect in orexin-2-saporin lesioned rats. Sleep 42(Supplement_1):A22-A23. doi: 10.1093/sleep/zsz067.053

Summary: Rats lesioned with Orexin-SAP in lateral hypothalamus produced narcoleptic-like behavior.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Nirogi R, Shinde A, Mohammed AR, Badange RK, Reballi V, Bandyala TR, Saraf SK, Bojja K, Manchineella S, Achanta PK, Kandukuri KK, Subramanian R, Benade V, Palacharla RC, Jayarajan P, Pandey S, Jasti V (2019) Discovery and development of N-[4-(1-Cyclobutylpiperidin-4-yloxy)phenyl]-2-(morpholin-4-yl)acetamide Dihydrochloride (SUVN-G3031): A novel, potent, selective, and orally active histamine H3 receptor inverse agonist with robust wake-promoting activity. J Med Chem 62(3):1203-1217. doi: 10.1021/acs.jmedchem.8b01280

Objective: To discover and develop a therapeutic for human sleep disorders.

Summary: Histamine H3 Receptor Inverse Agonist demonstrated high receptor occupancy and marked wake promoting effects with decreased REM sleep in Orexin-B-SAP lesioned rats. This study supports its potential therapeutic utility in treating human sleep disorders.

Usage: Injections (490 ng/0.8 μl) were made bilaterally to the lateral hypothalamus.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Daripelli S, Bhayrapuneni G, Tirumalesetty C, Benade V, Subramanian R, Petlu S, Praveena N, Jayarajan P, Shinde A, Badange R, Bhatta V, Nirogi R (2018) SUVN-G3031, H3 receptor inverse agonist produces wake promoting activity in rats with hypocretin-2-saporin lesions of the lateral hypothalamus. Neuroscience 2018 Abstracts 679.23 / VV4. Society for Neuroscience, San Diego, CA.

Summary: Numerous studies have demonstrated that brain histamine plays a crucial role in maintenance of wakefulness, attention, learning and other cognitive processes. SUVN-G3031, a potent H3 receptor inverse agonist is being developed for the treatment of narcolepsy and other sleep related disorders. SUVN-G3031 is one of the lead molecules with hKi of 8.7 nM and has more than 100 fold selectivity against the related GPCRs. SUVN-G3031 exhibited desired pharmacokinetic properties and brain penetration. SUVN-G3031 blocked R-α-methylhistamine induced water intake and increased tele-methylhistamine levels in brain and cerebrospinal fluid. A single oral administration of SUVN-G3031 produced significant increase in acetylcholine, histamine, dopamine and norepinephrine levels in the cortex. SUVN-G3031 produced wake promoting activity in male Wistar rats. In the present study, effects of SUVN-G3031 on sleep/ wake profile were evaluated in rats with lateral hypothalamic lesion using neurotoxin hypocretin-2-saporin. Narcoleptic-like sleep behavior was observed in rats injected with hypocretin-2-saporin in lateral hypothalamus. SUVN-G3031 produced significant increase in wakefulness with concomitant decrease in rapid eye movement (REM) sleep in these animals. These results are in agreement with electroencephalography (EEG) studies carried out in healthy male Wistar rats. Results from the current study and the neurotransmitter modulations produced by SUVN-G3031 provide a strong basis for the potential of SUVN-G3031 in treatment of sleep related disorders. First in human, Phase 1 studies for SUVN-G3031 are completed underUS IND and SUVN-G3031 has shown desirable pharmacokinetic profile with safety and tolerability in healthy human volunteers. Phase 2 study for narcolepsy is currently being planned.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Oliveira LM, Falquetto B, Moreira TS, Takakura AC (2018) Orexinergic neurons are involved in the chemosensory control of breathing during the dark phase in a Parkinson’s disease model. Exp Neurol 309:107-118. doi: 10.1016/j.expneurol.2018.08.004

Objective: To determine the involvement of orexin cells from the lateral hypothalamus/perifornical area (LH/PeF) on breathing.

Summary: The degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase.

Usage: For lesions of LH/PeF, two injections of Orexin-B-SAP or Rabbit IgG-SAP (100 ng/μl) were made into the lateral hypothalamus / perifornical area (LH/PeF).

Related Products: Orexin-B-SAP (Cat. #IT-20), Rabbit IgG-SAP (Cat. #IT-35)

Arias-Carrion O, Ortega-Robles E, de Celis-Alonso B, Palasz A, Mendez-Rojas MA, Salas-Pacheco J, Murillo-Rodriguez E (2018) Depletion of hypocretin/orexin neurons increases cell proliferation in the adult subventricular zone. CNS Neurol Disord Drug Targets 17:106-112. doi: 10.2174/1871527317666180314115623

Objective: To establish the relationship between the depletion of orexin neurons and the number of proliferating cells in the subventricular zone.

Summary: The adult subventricular zone is affected by orexinergic signaling, the functional implication of which must be further elucidated.

Usage: 90 ng of Orexin-SAP or pyrogen-free saline was stereotaxically injected into the lateral hypothalamus (3.2 caudal, 1.7 lateral to bregma, 8.1 ventral to the skull surface) of male Wistar rats.

Related Products: Orexin-B-SAP (Cat. #IT-20)