Targeting Topics 09q4

Evaluation of side effects through selective ablation of the mu opioid receptor expressing descending nociceptive facilitatory neurons in the rostral ventromedial medulla with dermorphin-saporin

Cao F, Chen SS, Yan XF, Xiao XP, Liu XJ, Yang SB, Xu AJ, Gao F, Yang H, Chen ZJ, Tian YK

Neurotoxicology 30(6):1096-1106, 2009.

Selective ablation of rostral ventromedial (RVM) neurons expressing mu opioid receptors has been suggested as a treatment for pathological pain. This work investigated the side effects of a 0.5-µg injection of dermorphin-SAP (Cat. #IT-12) into the RVM. Saporin (Cat. #PR-01) was used as a control. Lesioned animals experienced a temporary increase in heart rate and systolic blood pressure, and mild microglial responses, but even these soon returned to normal. The data suggest this system has potential as a target for pain therapeutics.

Septal grafts restore cognitive abilities and amyloid precursor protein metabolism

Aztiria E, Cataudella T, Spampinato S, Leanza G

Neurobiol Aging 30(10):1614-1625, 2009.

It is suspected that there is a connection between the loss of cortical cholinergic input and the presence of β-amyloid precursor protein (APP) in Alzheimer’s disease. After injecting 5 µg of 192-IgG-SAP (Cat. #IT-01) into the lateral ventricles of rats, the animals were given cholinergic-rich septal tissue grafts. The animals that received the grafts were able to restore APP levels to normal or near-normal, indicating that this type of therapy could at least slow cognitive dysfunction due to the lesion.

NGF is essential for hippocampal plasticity and learning

Conner JM, Franks KM, Titterness AK, Russell K, Merrill DA, Christie BR, Sejnowski TJ, Tuszynski MH

J Neurosci 29(35):10883-10889, 2009.

This work aimed to define NGF modulation of plasticity and function in adults. Rats received 50-ng injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum. Lesioned animals exhibited impaired retention of spatial memory and significantly reduced hippocampal long-term potentiation. These results indicate that NGF modulates neuronal plasticity and behavior by exerting effects on cholinergic projections to hippocampal and cortical targets.

Effects of chronic donepezil treatment and cholinergic deafferentation on parietal pyramidal neuron morphology

De Bartolo P, Gelfo F, Mandolesi L, Foti F, Cutuli D, Petrosini L

J Alzheimers Dis 17(1):177-191, 2009.

Donepezil has been shown to enhance cognitive functioning in both healthy patients and those suffering from dementia. This study examined whether donepezil treatment changes neocortical morphology in healthy or diseased brains. Rats received 4-µg bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the lateral ventricles. Various morphological parameters were analyzed demonstrating that in the absence of cholinergic neurons donepezil prevented the compensatory response rather than enhanced function.

A cholinergic-dependent role for the entorhinal cortex in trace fear conditioning

Esclassan F, Coutureau E, Di Scala G, Marchand AR

J Neurosci 29(25):8087-8093, 2009.

Higher cognitive involvement can be modeled through the use of trace conditioning in simple associative tasks. Rats received several 20-80-ng injections of 192-IgG-SAP (Cat. #IT-01) into the entorhinal cortex (EC) in order to clarify the mechanisms that allow learning through the association of events that occur at different times. Cholinergic depletion of the EC did not result in a training deficit, indicating that these cells are not necessary for trace conditioning.

Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons

Fargo KN, Foster AM, Sengelaub DR

Dev Neurobiol 69(12):825-835, 2009.

Previous work has demonstrated that testosterone treatment can prevent dendritic atrophy due to death of nearby motoneurons. This experiment examined whether this protection extends to motor activation. Rats received a 1-µg injection of CTB-SAP (Cat. #IT-14) into each of the right bulbocavernosus and levator ani muscles. Animals treated with testosterone preserved more of the activity duration than untreated animals, as well as no decrease in motoneuron recruitment.

Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice

Ho NF, Han SP, Dawe GS

BMC Neurosci 10:57, 2009.

The act of running can induce hippocampal neurogenesis. In this work the authors investigated whether running can offset the loss of septohippocamal cholinergic neurons caused by a lesion using mu p75-SAP (Cat. #IT-16). Mice received 3.6 µg of the toxin into each lateral ventricle. Although the number of surviving neurons was similar in both lesioned and control animals, most of the progenitor cells in the lesioned animals could not survive without cholinergic input.

Hypocretin-2 saporin lesions of the ventrolateral periaquaductal gray (vlPAG) increase REM sleep in hypocretin knockout mice

Kaur S, Thankachan S, Begum S, Liu M, Blanco-Centurion C, Shiromani PJ

PLoS One 4(7):e6346, 2009.

Not all connections between narcolepsy and orexin are understood, since orexin neurons are located in the lateral hypothalamus and some sleep functions are controlled by the brainstem. This experiment used 16.5-ng injections of orexin-SAP (Cat. #IT-20) into each side of the ventrolateral periaqueductal gray (v/PAG) to examine these connections. The results indicate that loss of orexin receptor-positive neurons in the v/PAG results in loss of inhibitory control over REM sleep, but does not cause cataplexy.

Role of layer 6 of V2 visual cortex in object-recognition memory

Lopez-Aranda MF, Lopez-Tellez JF, Navarro-Lobato I, Masmudi-Martin M, Gutierrez A, Khan ZU

Science 325(5936):87-89, 2009.

The authors examined the role of the V2 visual cortex in visual memory. Working with the prediction that object-recognition memory (ORM) control is centered in the V2 visual cortex, rats received 0.9-µg injections of OX7-SAP (Cat. #IT-02) into this area. Treatment with OX7-SAP eliminated virtually all neurons in layer 6 of area V2 of the visual cortex without damaging the hippocampus. The results indicate that this area of the visual cortex is important for ORM formation, but not storage.

Ketamine-induced deficit of auditory gating in the hippocampus of rats is alleviated by medial septal inactivation and antipsychotic drugs

Ma J, Tai SK, Leung LS

Psychopharmacol (Berl) 206(3):457-467, 2009.

Schizophrenic patients do not experience the usual diminished response to repeated stimuli, otherwise known as gating. Gating loss can be caused by the administration of some psychotomimetic drugs. This study used 170-ng injections of 192-IgG-SAP (Cat. #IT-01) to examine the effect of ketamine on sensory gating loss. Elimination of septohippocampal cholinergic neurons alleviated the disruption of auditory gating caused by ketamine.

Immunotoxic depletion of microglia in mouse hippocampal slice cultures enhances ischemia-like neurodegeneration

Montero M, Gonzalez B, Zimmer J

Brain Res 1291:140-152, 2009.

Data has shown microglia to be both neuroprotective and neurodegenerative in cerebral ischemia. This study presents a method for removing microglia from hippocampal slice cultures. Hippocampal slices from mouse were incubated with 13-nM Mac-1-SAP (Cat. #IT-06) for 3 to 7 days. The slices were then exposed to oxygen-glucose deprivation. Those cultures lacking microglia displayed significantly higher degeneration of CA1 pyramidal cells, indicating a neuroprotective role for microglia in this model.

T-cell reconstitution without T-cell immunopathology in two models of T-cell-mediated tissue destruction

Penaloza-MacMaster P, Masopust D, Ahmed R

Immunology 128(2):164-171, 2009.

Although antigen-specific T-cells are vital to adaptive immune responses, they also contribute to a variety of diseases. In this work the authors examined the possibility of selectively removing epitope-specific T cells while preserving immune function. Biotinylated MHC class I monomers were combined with streptavidin-ZAP (Cat. #IT-27) and used in a mouse transferable T-cell-dependent neurological disease model. This technique resulted in a dramatic reduction in targeted antigen-specific T-cells with no observable bystander toxicity.

Cellular Basis of Itch Sensation

Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF

Science 325(5947):1531-1534, 2009.

Whether itch and pain use separate neuronal pathways has long been a subject of debate. The authors injected 400 ng of bombesin-SAP (Cat. #IT-40) into the intrathecal space of mice and examined itch and pain behavior. Lesioned mice had dramatic deficits in all itch behavior tested regardless of the histamine-dependence of the itch. All pain behaviors, however, were left intact. These data indicate that the gastrin-releasing peptide receptor-expressing neurons are essential for itch transmission. (See Cover Article.)

Effects of the selective lesions of cholinergic septohippocampal neurons on different forms of memory and learning process

Dashniani MG, Beseliia GV, Maglakelidze GA, Burdzhanadze MA, Chkhikvishvili N

Georgian Med News 166):81-85, 2009.

The hippocampus is crucial for the ability to recollect everyday events and factual knowledge. Here the authors looked at the role of the septo-hippocampal cholinergic system of the medial septum in learning and memory. Rats received 200-ng injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The data suggest that although the septo-hippocampal region is essential for spatial learning, hippocampal acetylcholinesterase may not be essential for all types of hippocampal-dependent memory.

Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: Involvement of the HPA axis

Aisa B, Gil-Bea FJ, Marcos B, Tordera R, Lasheras B, Del Rio J, Ramirez MJ

Psychoneuroendocrinol 34(10):1495-1505, 2009.

Early adverse life events such as maternal separation (MS) can increase vulnerability to psychopathology as an adult. The authors administered bilateral intracerebroventricular 1-µg injections of 192-IgG-SAP (Cat. #IT-01) to MS rats, then analyzed choline acetyltransferase and acetylcholinesterase activity. Lesioned animals displayed reduced activity of both of these enzymes, as well as decreased glucocorticoid receptor density. The results suggest that vulnerability of basal forebrain cholinergic cells may be affected by the hypothalamic-pituitary-adrenal axis.

An anti-CD103 immunotoxin promotes long-term survival of pancreatic islet allografts

Zhang L, Moffatt-Bruce SD, Gaughan AA, Wang JJ, Rajab A, Hadley GA

Am J Transplant 9(9):2012-2023, 2009.

The integrin CD103 is suspected of promoting organ allograft rejection and graft-versus-host disease. A custom conjugation was done between the non-depleting CD103 antibody M290 and saporin. The conjugate was administered at 2.0 mg/kg to mice as an intraperitoneal injection (mouse IgG-SAP, Cat. #IT-18, was used as a control). The mice had previously received an islet transplant into a kidney capsule. Mice treated with M290-SAP were effectively depleted of CD103+ cells and had long-term acceptance of the allografts.

Medullary circuitry regulating rapid eye movement sleep and motor atonia

Vetrivelan R, Fuller PM, Tong Q, Lu J

J Neurosci 29(29):9361-9369, 2009.

Data concerning rapid-eye movement (REM) motor atonia in rats have not agreed with results seen in the large amount of data from cats. Here the authors traced the medullary networks in rats involved with the REM function. 120-300-ng injections of orexin-SAP (Cat. #IT-20) were administered to six different sites in the medulla. Ablation of orexin receptor-expressing neurons in one site in the ventromedial medulla resulted in intermittent loss of muscle atonia, indicating that glutaminergic neurons in this area are key components of the REM atonia circuit.

The Neurokinin-1 Receptor Modulates the Methamphetamine-Induced Striatal Apoptosis and Nitric Oxide Formation in Mice

Zhu J, Xu W, Wang J, Ali SF, Angulo JA

J Neurochem 111(3):656-668, 2009.

This study examined the role of neurokinin-1 receptors (NK-1r) on the methamphetamine-induced apoptosis of striatal neurons. 4 ng of SSP-SAP (Cat. #IT-11) or the control, saporin (Cat. #PR-01), was administered to the striatum of mice. Ablation of NK-1r-expressing striatal neurons resulted in a significant reduction of methamphetamine-induced apoptosis. The data suggest that the NK-1r circuitry in the striatum may be a target for treatment of methamphetamine abuse.