References

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.

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Walker JR, Ong A, Detloff MR (2019) Role of nociceptive afferent input on forelimb reaching and grasping behaviors in the spinal cord injured rat. Neuroscience 2019 Abstracts 572.09. Society for Neuroscience, Chicago, IL.

Summary: Individuals with spinal cord injury (SCI) suffer a loss of motor and sensory function. The current standard of care to recover fine motor control is rehabilitation focused on a combination of range of motion, aerobic, and strength training (ST). However, limited research has been conducted to determine the role of nociceptive afferent inputs from muscle on spinal plasticity and/or recovery of function. Using a rodent model of SCI strength training rehabilitation, we determined that motor training not only improves forelimb strength and fine motor function but also can modulate the development of neuropathic pain, suggesting that improvements in reaching and grasping may be due, in part, to plasticity of nociceptive afferents. To further explore this, Sprague-Dawley rats received injections of rIB4-conjugated saporin, mu p75-conjugated saporin or unconjugated (vehicle) into the cervical dorsal root ganglia unilaterally to eliminate non-peptidergic and peptidergic nociceptors. There is an uninjured cohort and a group with unilateral C5 SCI. Von Frey and Hargreaves’ tests were performed at baseline and several time points post-injection to assess the effcacy of the nociceptive elimination. Several measures of forelimb strength were recorded over time including the isometric pull task, a single pellet retrieval task and the Montoya staircase test. To confirm the depletion of peptidergic and non-peptidergic nociceptors following saporin injection and/or SCI, cervical DRGs and spinal cords were stained with antibodies against CGRP and isolectin-B4. An understanding of the role of nociceptors in spinal plasticity and functional motor and sensory recovery of SCI patients will guide future research and refine rehabilitation strategies to further improve their quality of life.

Related Products: IB4-SAP (Cat. #IT-10), mu p75-SAP (Cat. #IT-16)

Guyenet PG, Stornetta RL, Souza GMPR, Abbott SBG, Shi Y, Bayliss DA. (2019) The retrotrapezoid nucleus: Central chemoreceptor and regulator of breathing automaticity. Trends Neurosci 42(11):807-824. doi: 10.1016/j.tins.2019.09.002

Summary: This review describes the neurons of the retrotrapezoid nucleus (RTN), their transcriptome, developmental lineage, and anatomical projections. The authors also review their contribution to CO2 homeostasis and to the regulation of breathing automaticity during sleep and wake.

Usage: Local injection of SSP-SAP to kill RTN neurons.

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Li J, Xiang X, Xu H, Shi Y (2019) Cilostazol promotes angiogenesis and increases cell proliferation after myocardial ischemia–reperfusion injury through a camp-dependent mechanism. Cardiovasc Eng Technol 10(4):638-647. doi: 10.1007/s13239-019-00435-0 PMID: 31625080

Usage: western

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Kucinski A, Phillips KB, Koshy Cherian A, Sarter M (2020) Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071. Psychopharmacology (Berl) 237(1):137-153. doi: 10.1007/s00213-019-05354-5 PMID: 31620809

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Avrampou K, Pryce KD, Ramakrishnan A, Sakloth F, Gaspari S, Serafini RA, Mitsi V, Polizu C, Swartz C, Ligas B, Richards A, Shen L, Carr FB, Zachariou V (2019) RGS4 maintains chronic pain symptoms in rodent models. J Neurosci 39(42):8291-8304. doi: 10.1523/JNEUROSCI.3154-18.2019 PMID: 31308097

Usage: western

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Wercberger R, Basbaum AI (2019) Spinal cord projection neurons: A superficial, and also deep, analysis. Curr Opin Physiol 11:109-115. doi: 10.1016/j.cophys.2019.10.002

Summary: Modern approaches to map complex neural circuits require knowledge of the molecular language that defines cell type specificity. However, with few exceptions, NK1R remains the marker consistently used to define projection neurons and even to interrogate their contribution to pain and itch (Mantyh et al.) The first of two studies demonstrating that SP-SAP-mediated ablation of dorsal horn NK1R-expressing neurons reduces injury-induced hyperalgesia. (Carstens et al.) In this paper SP-SAP-mediated ablation of dorsal horn NK1R-expressing neurons reduced pruritogen-evoked scratching.

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See Also:

• Mantyh PW et al. Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278:275-279, 1997.
• Carstens EE et al. Dorsal horn neurons expressing NK-1 receptors mediate scratching in rats. Neuroreport 21:303-308, 2010.

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)

Martins JR, Reichhart N, Kociok N, Stindl J, Foeckler R, Lachmann P, Todorov V, Castrop H, Strauß O (2019) Systemic ß adrenergic stimulation/ sympathetic nerve system stimulation influences intraocular RAS through cAMP in the RPE. Exp Eye Res 189:107828. doi: 10.1016/j.exer.2019.107828 PMID: 31589840

Objective: To investigate whether systemic β-adrenergic stimulation of the retinal pigment epithelium (RPE) also modulates renin expression in the RPE.

Summary: In vitro analysis of renin gene expression using polarized porcine RPE showed that the activity of the renin promoter can be increased by cAMP stimulation (IBMX/forskolin) but was not influenced by angiotensin-2.

Usage: Immunohistochemistry; eye sections were labeled overnight at 4°C with Anti-AT-1R.

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Klotz L, Wendler O, Frischknecht R, Shigemoto R, Schulze H, Enz R (2019) Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses. FASEB J 33(12):13734-13746. doi: 10.1096/fj.201901543R PMID: 31585509

Usage: immunohistochemistry (1:150)

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