Targeting Topics 08q4

Tomoregulin internalization confers selective cytotoxicity of immunotoxins on prostate cancer cells.

Zhao XY, Liu HL, Liu B, Willuda J, Siemeister G, Mahmoudi M, Dinter H

Transl Oncol 1:102-109, 2008.

Tomoregulin is a type 1 transmembrane protein with a short cytoplasmic tail, and is found in the brain and prostate. After confirming cell surface localization by flow cytometry, and determining expression levels by whole-cell binding assays, the authors evaluated the use of tomoregulin as a target for immunotoxin therapy. Cells transfected with tomoregulin were treated with anti-tomoregulin + Mab-ZAP (IC50 = 160 pM; Cat. #IT-04) in vitro. The results demonstrate the potential for tomoregulin in prostate cancer treatment.

Reduced cholinergic status in hippocampus produces spatial memory deficits when combined with kainic acid induced seizures.

Craig LA, Hong NS, Kopp J, McDonald RJ

Hippocampus 18(11):1112-1121, 2008.

The loss of cholinergic neurons in the medial septum and seizures are both associated with Alzheimer’s disease. The authors investigated links between these factors using 192-IgG-SAP (Cat. #IT-01) and kainic acid. Rats received 0.15 µg of 192-IgG-SAP delivered to the medial septum and vertical limb of the diagonal band of Broca in four injections. Animals receiving both 192-IgG-SAP and kainic acid performed significantly worse in water maze tests than control animals, indicating that loss of cholinergic neurons and seizures interact in Alzheimer’s disease.

GDNF hyperalgesia is mediated by PLCgamma, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versican.

Bogen O, Joseph EK, Chen X, Levine JD

Eur J Neurosci 28:12-19, 2008.

C-fiber nociceptors have been divided into NGF and GDNF classes. Here the authors examined the function of an isolectin B4-binding subpopulation of these nocicepetors. Rats received 40 ng of IB4-SAP (Cat. #IT-10) into the intrathecal space between the fifth and sixth lumbar vertebrae. The results demonstrate that GDNF sensitizes IB4+ C-fiber nociceptors and causes mechanical hyperalgesia.

Amygdala intercalated neurons are required for expression of fear extinction.

Likhtik E, Popa D, Apergis-Schoute J, Fidacaro GA, Pare D

Nature 454:642-645, 2008.

Scientists have been using fear learning in animals to study human anxiety disorders. In order to investigate the contribution of amygdala plasticity to fear learning, rats received 0.25-µl bilateral infusions of 3-µM dermorphin-SAP (Cat. #IT-12) into the amygdala. Blank-SAP (Cat. #IT-21) was used as a control. Lesioned rats displayed extinction expression deficits, indicating that the eliminated intercalated amygdala neurons play a large role in the extinction process. (see cover story)

IB4 afferent sprouting contributes to bladder dysfunction in spinal rats.

Zinck ND, Downie JW

Exp Neurol 213:293-302, 2008.

Spinal cord injury can cause inefficient bladder function, but the direct cause is not well understood. Most work has focused on afferent neurons that contain CGRP and respond to NGF. Here the authors investigate the role of isolectin B4 (IB4)-expressing neurons that are supported by GDNF. Rats received intrathecal injections of either 2.4 µg IB4-SAP (Cat. #IT-10) or 3 µg control saporin (Cat. #PR-01). The data suggest that IB4-afferent sprouting is involved in bladder dysfunction following spinal cord transection.

Renal sympathoinhibition induced by hypernatremia: Involvement of A1 noradrenergic neurons.

Pedrino GR, Rosa DA, Korim WS, Cravo SL

Auton Neurosci 142(1-2):55-63, 2008.

A1 noradrenergic neurons in the caudal ventrolateral medulla (CVLM) are thought to contribute to body fluid homeostasis and cardiovascular regulation. In order to examine the role these neurons play on inhibition of renal sympathetic nerve activity (RSNA) induced by hypertonic saline infusion, rats received 6.3 ng of anti-DBH-SAP (Cat. #IT-03) into the CVLM. Saporin (Cat. #PR-01) was used as a control. Animals treated with anti-DBH-SAP displayed lengthened duration of the pressor response and sustained RSNA.

Lesions of medullary catecholaminergic neurons increase salt intake in rats.

Colombari DS, Pedrino GR, Freiria-Oliveira AH, Korim WS, Maurino IC, Cravo SL

Brain Res Bull 76:572-578, 2008.

Catecholaminergic neurons in the caudal ventrolateral medulla (CVLM) are thought to contribute to cardiovascular regulation and body fluid homeostasis. Bilateral 6.3-ng injections of anti-DBH-SAP (Cat. #IT-03) were administered to the CVLM of rats. Saporin (Cat. #PR-01) was used as a control. After lesioning and challenge with either furosemide/captopril or water deprivation, intake of 0.3 M NaCl and water were observed. The data indicate medullary catecholaminergic neurons play an inhibitory role in sodium appetite.

Effects of hypocretin (orexin) neuronal loss on sleep and extracellular adenosine levels in the rat basal forebrain.

Murillo-Rodriguez E, Liu M, Blanco-Centurion C, Shiromani PJ

Eur J Neurosci 28(6):1191-1198, 2008.

Adenosine levels in the basal forebrain are thought to regulate the waxing and waning of sleep drive. Rats received bilateral 100-ng injections of orexin-SAP (Cat. #IT-20) into the lateral hypothalamus – resulting in a 94% loss of orexin-containing neurons. Lesioned animals displayed several changes in sleep characteristics, but no increase of adenosine levels after sleep deprivation. The results indicate that sleep changes due to orexin-SAP lesioning occur independently of adenosine levels.

Hyperphagia and obesity produced by arcuate injection of NPY-saporin do not require upregulation of lateral hypothalamic orexigenic peptide genes.

Li AJ, Dinh TT, Ritter S

Peptides 29(10):1732-1739, 2008.

It has already been shown that lesioning NPY receptor-expressing cells in the arcuate nucleus (Arc) and basomedial hypothalamus produces obesity in rats. The authors examined the contribution of orexigenic peptides, orexins, and melanocortin-concentrating hormone to the lesion effects. Rats received bilateral 24 ng injections of NPY-SAP (Cat. #IT-28) into the dorsal border of the Arc. Blank-SAP (Cat. #IT-21) was used as a control. The data suggest that obesity produced by NPY-SAP lesion is different than dietary obesity or obesity associated with leptin or leptin receptor deficiency.

The neonatal injury-induced spinal learning deficit in adult rats: central mechanisms.

Young EE, Baumbauer KM, Hillyer JE, Patterson AM, Hoy KC, Jr., Mintz EM, Joynes RL

Behav Neurosci 122:589-600, 2008.

This report examined whether neonatal injuries had any contralateral effects in adult life, and evaluated the role of the NK1 receptor of adult animals that had been subjected to neonatal trauma. Rats were injected with 5 µl of SP-SAP (Cat. #IT-07, 30 ng/µl, 100 ng/µl, or 300 ng/µl) into the intrathecal space. Blank-SAP (Cat. #IT-21) was used as a control. The results indicate both that injury effects are isolated in the injured limb, and NK1 receptor-expressing cells are involved in processing this pain.

Environmental Enrichment Provides a Cognitive Reserve to be Spent in the Case of Brain Lesion.

Mandolesi L, De Bartolo P, Foti F, Gelfo F, Federico F, Leggio MG, Petrosini L

J Alzheimers Dis 15(1):11-28, 2008.

The cognitive reserve model suggests individuals can develop resources that reduce the risk of later cognitive impairment. This theory was tested by raising rats in standard vs. enriched environments then lesioning the animals with 192-IgG-SAP (Cat. #IT-01). A total of 0.8 µg of 192-IgG-SAP was administered in bilateral injections, followed by various behavioral tests. It was found that animals raised in an enriched environment had reduced cognitive impairment following forebrain lesions.

Noradrenergic inputs to the paraventricular hypothalamus contribute to hypothalamic-pituitary-adrenal axis and central Fos activation in rats after acute systemic endotoxin exposure.

Bienkowski MS, Rinaman L

Neuroscience 156(4):1093-1102, 2008.

Noradrenergic (NA) neurons in the central nervous system are activated during the immune response to systemic lipopolysaccharide (LPS). The authors tested whether these neurons with axonal inputs to the paraventricular nucleus (PVN) were necessary for LPS-directed Fos expression and increase of plasma corticosterone. Rats received 44-ng bilateral injections of anti-DBH-SAP (Cat. #IT-03) into the medial PVN then were challenged with i.p. LPS. Lesioned animals had attenuated Fos activation and smaller than normal increases in plasma corticosterone.