References

Silva T, Takakura A, Moreira T (2016) Acute hypoxia activates hypothalamic paraventricular nucleus-projecting catecholaminergic neurons in the C1 region. Exp Neurol 285:1-11. doi: 10.1016/j.expneurol.2016.08.016

Summary: Catecholaminergic C1 cells reside in the rostral and intermediate portions of the ventrolateral medulla (RVLM) and can be activated by hypoxia. These neurons regulate the hypothalamic pituitary axis via direct projections to the hypothalamic paraventricular nucleus (PVH) and regulate the autonomic nervous system via projections to sympathetic and parasympathetic preganglionic neurons. The present results suggest that catecholaminergic C1-PVH projection is hypoxia-sensitive and the pathway between these two important brain areas can be one more piece in the complex puzzle of neural control of autonomic regulation during hypoxia. Male Wistar rats were injected with the targeted toxin Anti-DβH-SAP (Cat. #IT-03), 21 ng/100 nl, or saline, unilaterally into the PVH using the following coordinates: 1.2 mm caudal to bregma, 0.4 mm lateral to the midline and 7.8 mm below the dura mater. The author’s work adds a piece in the complex puzzle of the physiological role of the C1 cells by showing that this catecholaminergic group of cells must be activated only in emergency situations such as acute hypoxia, producing autonomic, metabolic, and neuroendocrine responses designed to help the organism survive major acute physical stresses.

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

Coradazzi M, Gulino R, Fieramosca F, Falzacappa L, Riggi M, Leanza G (2016) Selective noradrenaline depletion impairs working memory and hippocampal neurogenesis. Neurobiol Aging 48:93-102. doi: 10.1016/j.neurobiolaging.2016.08.012

Summary: Neuronal loss in the locus coeruleus (LC) of Alzheimer’s patients is well known, but the contribution of LC-derived noradrenergic afferents to learning and memory function is unknown. To model noradrenergic neuron degeneration in the LC, rats were bilaterally injected directly into the LC with 0.2 ug of Anti-DBH-SAP (Cat. #IT-03). Lesioned and sham-lesioned animals were tested behaviorally and exhibited robust working memory deficits but lesioning did not affect reference memory. They concluded that ascending noradrenergic afferents might be involved in more complex aspects of working memory, possibly via newly generated progenitors in the hippocampus.

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

Kucinski A, de Jong IEM, Sarter M (2017) Reducing falls in Parkinson’s disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. Eur J Neurosci 45:217-231.. doi: 10.1111/ejn.13354

Objective: To assess the effects of treatment on MCMCT performance and attention in DL rats. The combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was use because it has been reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease.

Summary: This treatment may reduce fall propensity in patients.

Usage: 192-IgG-SAP aCSF infused bilaterally (120 ng/uL; 0.5 uL/hemisphere).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Araldi D, Ferrari L, Levine J (2016) Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming. Pain 157:1773-1782. doi: 10.1097/j.pain.0000000000000581

Summary: The present study explored the possibility that, like MOR and A1-adenosine receptor agonists, triptans would also induce type II hyperalgesic priming. In addition, they explored the 5-HT receptor subtypes at which triptans act (5-HT1B, 5-HT1D and 5-HT7) to induce priming. They report that while sumatriptan, a prototypical 5-HT1B/D receptor agonist induces hyperalgesic priming, this priming meets the criteria for type I rather than type II priming. Isolectin B4 (IB4)-saporin (Cat. #IT-10), was diluted in saline, and a dose of 3.2 μg, in a volume of 20 μL was administered intrathecally to rats. The neurotoxin [Sar9,Met(O2) 11]-substance P-saporin (SSP-Saporin, Cat. #IT-11) was diluted in saline, and a dose of 100 ng, in a volume of 20 μL was administered intrathecally. In a model of pain chronification, sumatriptan induces both mechanical hyperalgesia at the site of injection and type I hyperalgesic priming, in nociceptors innervating the cutaneous injection site.

Related Products: IB4-SAP (Cat. #IT-10), SSP-SAP (Cat. #IT-11)

Ngo M, Han A, Lakatos A, Sahoo D, Hachey S, Weiskopf K, Beck A, Weissman I, Boiko A (2016) Antibody therapy targeting CD47 and CD271 effectively suppresses melanoma metastasis in patient-derived xenografts. Cell Rep 16:1701-1716. doi: 10.1016/j.celrep.2016.07.004

Summary: The high rate of metastasis and recurrence among melanoma patients indicates the presence of cells within melanoma that have the ability to both initiate metastatic programs and bypass immune recognition. The authors identified CD47 as a regulator of melanoma tumor metastasis and immune evasion. The study involved antibody-mediated blockade of CD47 coupled with targeting of CD271+ melanoma cells by way of ME20.4-SAP (Cat. #IT-15). Mice bearing human melanoma tumor (M213 or M727) were randomized into four treatment groups with one of those groups receiving treatment with ME20.4-SAP. 1 ug in 50 ul volumes were injected directly into the center mass of the tumor once every 2 days. A therapeutic effect was observed where tumor metastasis in patient-derived xenografts was strongly inhibited when treated with the combination of antibody-mediated blockade of CD47 and targeted with ME20.4-SAP.

Related Products: ME20.4-SAP (Cat. #IT-15)

Kumar J, Rajkumar R, Lee L, Dawe G (2016) Nucleus incertus contributes to an anxiogenic effect of buspirone in rats: Involvement of 5-HT1A receptors. Neuropharmacology 110:1-14. doi: 10.1016/j.neuropharm.2016.07.019

Summary: The nucleus incertus (NI) is involved in stress and anxiety responses. The NI is a cluster of GABAergic neurons in the brainstem, and coexpresses CRF, 5-HT1A and D2 receptors. Buspirone is a partial agonist of 5-HT1A receptors, an antagonist of D2 receptors, and activates the NI. Buspirone is an anti-anxiety drug, but preclinical studies showed that it induces anxiety at high doses. To see if the NI is necessary for the anxiogenic effects of high doses of buspirone, rats were bilaterally injected with 86 ng of CRF-SAP (Cat. #IT-13) into the NI. Blank-SAP (Cat. #IT-21) was used as a control. NI lesioning alone had an anxiogenic effect in several anxiety screening tests compared to sham-lesioned rats, which suggests that the NI reduces anxiety physiologically. Lesioning with CRF-SAP reduced the anxiogenic effects of intra-NI injections of buspirone. No significant difference in the anxiety screening tests resulted from injecting quinpiole, a D2 agonist, which suggests that the 5HT1A receptors in the NI are involved in the anxiogenic effects of buspirone.

Related Products: CRF-SAP (Cat. #IT-13), Blank-SAP (Cat. #IT-21)

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Hay C, Sult E, Huang Q, Mulgrew K, Fuhrmann S, McGlinchey K, Hammond S, Rothstein R, Rios-Doria J, Poon E, Holoweckyj N, Durham N, Leow C, Diedrich G, Damschroder M, Herbst R, Hollingsworth R, Sachsenmeier K (2016) Targeting CD73 in the tumor microenvironment with MEDI9447. Oncoimmunology 5:e1208875. doi: 10.1080/2162402X.2016.1208875

Summary: MEDI9447 is a human monoclonal antibody that is specific for the ectoenzyme CD73 and currently undergoing Phase I clinical trials. Here the authors show that MEDI9447 is a potent inhibitor of CD73 ectonucleotidase activity, with wide ranging immune regulatory consequences. MEDI9447 results in relief from adenosine monophosphate (AMP)-mediated lymphocyte suppression in vitro and inhibition of mouse syngeneic tumor growth in vivo. In contrast with other cancer immunotherapy agents such as checkpoint inhibitors or T-cell agonists, MEDI9447 drives changes in both myeloid and lymphoid infiltrating leukocyte populations within the tumor microenvironment of mouse models. In vitro experiments validating the internalization of antibodies into cell lines MDA-MB-231 and 4T1 were measured using the Fab-ZAP human antibody internalization kit (Cat. #KIT-51-Z). Combination data showing additive activity between MEDI9447 and anti-PD-1 antibodies using human cells in vitro and mouse tumor models further demonstrate the potential value of relieving adenosine-mediated immunosuppression. Based on these data, a Phase I study to test the safety, tolerability, and clinical activity of MEDI9447 in cancer patients was initiated (NCT02503774).

Related Products: Fab-ZAP human (Cat. #IT-51)

Lim J, Stafford B, Nguyen P, Lien B, Wang C, Zukor K, He Z, Huberman A (2016) Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat Neurosci 19:1073-1084. doi: 10.1038/nn.4340 PMID: 27399843

Summary: Axons in the CNS fail to regenerate after injury. Scientists sought to identify strategies that would allow retinal ganglion cell (RGC) axons to regenerate in the eye-to-brain pathway, and if that was possible, whether the axons could reconnect with their correct targets and restore visual function. It was previously shown that increasing mTOR signaling could trigger RGC axon regeneration. Several conditions were tested, but combining increased mTOR signaling and then exposing mice to high-contrast visual stimulation daily for 3 weeks scientists after optic nerve crush resulted in long distance RGC axon regeneration, re-innervation of the brain and partial recovery of a subset of visual behaviors. A 1:1000 dilution of Anti-Melanopsin (Cat. #AB-N38) was used for the immunohistochemical analysis of retinas, optic nerves and brain tissue.

Related Products: Melanopsin Rabbit Polyclonal (Cat. #AB-N38)

Gilabert-Oriol R, Thakur M, Haussmann K, Niesler N, Bhargava C, Görick C, Fuchs H, Weng A (2016) Saponins from Saponaria officinalis L. augment the efficacy of a Rituximab-immunotoxin. Planta Med 82:1525-1531. doi: 10.1055/s-0042-110495

Summary: It is known that triterpenoidal saponins that come from Saponaria officinalis, the plant that saporin comes from, increases the cytotoxicity of saporin by modulating its intracellular trafficking. Investigators wanted to know if this could increase the therapeutic affect of Rituximab-Saporin. In the presence of saponins, Rituximab-Saporin had a 700-fold increase in efficacy. Concentrations of 0.0001-1nM of Anti-CD22-SAP (Cat. #IT-37) and 0.001-10nM of Anti-CD25-SAP (Cat. #IT-24) were also tested in vitro with saponins for comparison. They saw a 170-fold and 25-fold increase in cytotoxicity, respectively. All conjugates were tested on Ramos cells, and differing levels of receptor expression could explain the drastic differences in cytotoxicity enhancement.

Related Products: Anti-CD22-SAP human (Cat. #IT-37), Anti-CD25-SAP human (Cat. #IT-24)

Palchaudhuri R, Saez B, Hoggatt J, Schajnovitz A, Sykes D, Tate T, Czechowicz A, Kfoury Y, Ruchika F, Rossi D, Verdine G, Mansour M, Scadden D (2016) Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 34:738-745. doi: 10.1038/nbt.3584

Summary: To demonstrate correction of a clinically relevant disease, we employed CD45-SAP in a mouse model of sickle cell anemia and demonstrated our method achieved >90% donor cell chimerism, all mice in three groups (18/18), resulting in complete disease correction (red blood cell counts, hemoglobin levels, hematocrit levels and reticulocyte frequencies were returned to normal). If these pre-clinical results can be successfully translated to the clinic, it would greatly reduce conditioning-related toxicities and expand the use of hematopoietic stem cell transplantation.

Related Products: Streptavidin-ZAP (Cat. #IT-27), Anti-CD45.2-SAP (Cat. #IT-91)

Read the featured article in Targeting Trends.