targeted-toxins

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)

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)

Harris RB (2019) Leptin receptor activity in the nucleus of the solitary tract increases forebrain leptin sensitivity. Neuroscience 2019 Abstracts 591.04. Society for Neuroscience, Chicago, IL.

Summary: We previously reported that fourth ventricle infusions of leptin that cause weight loss are associated with an increase in hypothalamic phosphorylation of signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor (ObRb) activation, implying an integrated response to central leptin. This study tested the impact of ObRb activity in the nucleus of the solitary tract (NTS) on sensitivity to leptin in the forebrain. Leptin-Saporin (Lep-Sap) injections were used to delete ObR- expressing neurons in the NTS of 300g male Sprague Dawley rats. Controls were injected with Blank-Saporin (Blk-Sap). Loss of NTS ObR was confirmed with RNAScope in situ hybridization and pSTAT3 response to peripheral leptin in representative Lep- Sap rats. Experimental rats were fitted with 3rd ventricle (3V) guide cannula 12 days after Lep-Sap or Blk-Sap injections. Nine days later cannula placement was tested with Angiotensin II and rats were adapted to calorimeter cages for 4 days. Lep-Sap had no effect on body weight. To test leptin responsiveness rats were food deprived for 5 hours and at 5 p.m. they received 3V injections of 0, 0.05, 0.1, 0.25 or 0.5 μg leptin. Food was returned at 6 p.m., the start of the dark period. Each rat received the injections in random order at 4 day intervals. At the end of the experiment NTS pSTAT3 was used to confirm effcacy of Lep-Sap injections. Seven Lep-Sap and 6 control Blk-Sap rats completed the experiment. There was a dose-dependent inhibition of food intake in Blk-Sap rats, but only 0.5 μg leptin inhibited intake of Lep-Sap rats. Intake was inhibited during the 24 hours following injection and was not compensated for so that cumulative intake was inhibited for 60 hours post-injection. Energy expenditure was not different between groups and respiratory exchange ratio tended to follow food intake. These data suggest that leptin- induced inhibition of food intake is mediated by an integrated network involving both the forebrain and hindbrain and that activation of NTS ObRb lowers the threshold for leptin responsiveness in the forebrain.

Related Products: Leptin-SAP (Cat. #IT-47)