targeted-toxins

Souza GMPR, Stornetta RL, Stornetta DS, Abbott SBG, Guyenet PG (2019) Contribution of the retrotrapezoid nucleus and carotid bodies to hypercapnia- and hypoxia-induced arousal from sleep. J Neurosci 39(49):9725-9737. doi: 10.1523/JNEUROSCI.1268-19.2019

Objective: To examine the contribution of two lower brainstem nuclei that could be implicated in CO2 and hypoxia-induced arousal.

Summary: RTN, a brainstem nucleus that mediates the effect of brain acidification on breathing, also contributes to arousal elicited by CO2 but not hypoxia.

Usage: To ablate the retrotrapezoid nucleus (RTN), SSP-SAP was administered (2.4 ng) through bilateral injections via a dorsal craniotomy.

Related Products: SSP-SAP (Cat. #IT-11)

Thorsdottir D, Cruickshank NC, Einwag Z, Hennig GW, Erdos B (2019) BDNF downregulates β-adrenergic receptor-mediated hypotensive mechanisms in the paraventricular nucleus of the hypothalamus. Am J Physiol Heart Circ Physiol 317(6):H1258-H1271. doi: 10.1152/ajpheart.00478.2019

Objective: To determine whether BDNF increases blood pressure in part by diminishing inhibitory hypotensive input from nucleus of the solitary tract (NTS) catecholaminergic neurons projecting to the PVN.

Summary: BDNF, a key hypothalamic regulator of blood pressure, disrupts catecholaminergic signaling between the NTS and the PVN by reducing the responsiveness of PVN neurons to inhibitory hypotensive β-adrenergic input from the NTS.

Usage: Bilateral NTS injections of sterile PBS (for control) or Anti-DBH-SAP (22 ng).

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Goodman RL, He W, Lopez JA, Bedenbaugh MN, McCosh RB, Bowdridge EC, Coolen LM, Lehman MN, Hileman SM (2019) Evidence that the LH surge in ewes involves both neurokinin B–dependent and –independent actions of kisspeptin. Endocrinology 160(12):2990-3000. doi: 10.1210/en.2019-00597

Objective: To determine if NKB is involved in the RCh of the ewe in the LH surge.

Summary: NKB signaling in the RCh increases kisspeptin levels critical for the full amplitude of the LH surge in the ewe, but kisspeptin release occurs independently of retrochiamatic area (RCh) input at the onset of the surge to initiate GnRH secretion.

Usage: Bilaterial injections in the RCh of either NK3-SAP or Blank-SAP.

Related Products: NKB-SAP (Cat. #IT-63), Blank-SAP (Cat. #IT-21)

Toledo C, Andrade DC, Díaz HS, Pereyra KV, Schwarz KG, Díaz-Jara E, Oliveira LM, Takakura AC, Moreira TS, Schultz HD, Marcus NJ, Del Rio R (2019) Rostral ventrolateral medullary catecholaminergic neurones mediate irregular breathing pattern in volume overload heart failure rats. J Physiol 597(24):5799-5820. doi: 10.1113/JP278845

Objective: To investigate the potential contribution of RVLM‐C1 neurons to irregular breathing.

Summary: Findings suggest that RVLM‐C1 neurons play a pivotal role in breathing irregularities in volume overload HF, and mediate the sympathetic responses induced by acute central chemoreflex activation.

Usage: Anti-DBH-SAP was used to selectively lesion RVLM‐C1 neurons. Reduction (∼65%) of RVLM‐C1 neurons resulted in attenuation of irregular breathing, decreased apnea‐hypopnea incidence and improved cardiac autonomic control.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Díaz HS, Andrade DC, Toledo C, Lucero C, Arce-Álvarez A, Del Rio R (2019) Episodic stimulation of central chemoreflex elicits long-term breathing disorders and autonomic imbalance in heart failure rats. Eur Respir J 54(suppl 63):OA4936. doi: 10.1183/13993003.congress-2019.OA4936

Objective: To determine the role of CC in the development of cardiorespiratory dysfunction in a HF model.

Summary: Rats were exposed to pisodic hypercapnic stimulation (EHS) The effects of EHS in rats with heart failure were attenuated by SSP-SAP treatment.

Usage: Selective destruction of chemoreceptor neurons within the retrotapezoid nucleus (RTN) was performed via SSP-SAP injections (0.6 ng/30 nL).

Related Products: SSP-SAP (Cat. #IT-11)

Ueda H (2019) Systems pathology of neuropathic pain and fibromyalgia. Biol Pharm Bull 42(11):1773-1782. doi: 10.1248/bpb.b19-00535

Related Products: Mac-1-SAP mouse/human (Cat. #IT-06)

Tominaga M, Kusube F, Honda K, Komiya E, Takahashi N, Naito H, Suga Y, Takamori K (2019) OP11: Role of spinal cholecystokinin receptor 2 in alloknesis models. Itch 4:1-62. doi: 10.1097/itx.0000000000000030

Objective: To determine the detailed molecular and cellular mechanisms that induce alloknesis via the spinal CCK2 receptor.

Summary: Ablation of spinal CCK receptor-expressing cells by i.t. injection of CCK-SAP attenuated CCK8S-induced alloknesis in comparison with Blank-SAP control mice.

Usage: Intrathecal injection

Related Products: CCK-SAP (Cat. #IT-31), Blank-SAP (Cat. #IT-21)

Herman JP (2020) Corticolimbic stress regulatory circuits, hypothalamo–pituitary–adrenocortical adaptation, and resilience. Chen A (Ed.): Stress Resilience 291-309. Academic Press doi: 10.1016/B978-0-12-813983-7.00019-7

Summary: Review. Immunolesion of paraventricular nucleus (PVN)-projecting norepinephrine (NE) neurons with Anti-DBH-SAP attenuates acute stress reactivity (interestingly, to restraint), but it does not inhibit somatic or HPA axis responses to stress in any simple way (Flak et al.). PVN-projecting NE neurons appear to be responsible for acute responses to systemic stressors, but they do not appear to be important in mediating effects of chronic stress (Ritter et al.).

Usage: Flak et al. injected 8.82 ng of Anti-DBH-SAP into the PVN. Ritter et al. injected 42 ng into the PVN.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

See Also:

• Flak J et al. Role of paraventricular nucleus-projecting norepinephrine/epinephrine neurons in acute and chronic stress. Eur J Neurosci 39:1903-1911, 2014.
• Ritter S et al. Immunotoxin lesion of hypothalamically projecting norepinephrine and epinephrine neurons differentially affects circadian and stressor-stimulated corticosterone secretion. Endocrinology 144(4):1357-1367, 2003.

Kiuchi MG, Chen S, Carnagarin R, Matthews VB, Schlaich MP (2019) Renal denervation for treating congenital long QT syndrome: Shortening the QT interval or modulating sympathetic tone?. Europace 21(11):1755-1756. doi: 10.1093/europace/euz251

Summary: Targeted ablation of cardiac sympathetic neurons (TACSN) through CTB-SAP injection in the left stellate ganglion (LSG), inhibited its activation, improved sympathetic remodelling, and restored cardiac autonomic balance.

See: Xiong L et al. Targeted ablation of cardiac sympathetic neurons improves ventricular electrical remodelling in a canine model of chronic myocardial infarction. Europace 20(12):2036-2044, 2018.

Related Products: CTB-SAP (Cat. #IT-14)

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)