Targeting Topics 11q2

Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion.

Antonini V, Marrazzo A, Kleiner G, Coradazzi M, Ronsisvalle S, Prezzavento O, Ronsisvalle G, Leanza G.

J Alzheimers Dis, 24(3):569-586, 2011.

Sigma-1 receptor agonists such as (-)-MR22 are potential therapeutic drugs for the treatment of cognitive and affective disorders. To model a cognitive disorder, rats received 81-ng bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum/vertical limb of the diagonal band of Broca, and 130-ng bilateral injections into the nucleus basalis magnocellularis. Lesioned animals also were treated with pre-aggregated amyloid peptide. Pretreatment with (-)-MR22 reversed cognitive impairments in the double-lesioned animals, indicating the potential use of sigma-1 receptor agonists as protective agents.

Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons.

Gibbs RB, Chipman AM, Nelson D.

Horm Behav 59(4)L503-511, 2011.

Among the beneficial effects of estrogen on the brain are improved cognitive performance and prevention of age-related cognitive decline. These positive effects diminish over time following loss of ovarian function. To investigate the role of cholinergic neurons in this process, rats received 96-250 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septal nucleus followed by a cholinergic enhancer and estradiol therapy. The dual therapy had a positive effect on partially lesioned animals, but did not improve the performance of animals with severe lesions.

Neurotrophin/receptor expression in urinary bladder of mice with overexpression of NGF in urothelium.

Girard BM, Malley SE, Vizzard MA.

Am J Physiol Renal Physiol 300(2):F345-55, 2011.

Chronic overexpression of nerve growth factor (NGF) in the urinary bladder results in neuronal sprouting, increased voiding frequency, and referred somatic hypersensitivity. The authors investigated several growth factor and receptor responses to chronic overexpression of NGF. A p75 antibody (Cat. #AB-N01) was used to obtain the immunohistochemistry data. The data suggest that changes due to NGF overexpression may be a compensatory attempt to reduce voiding frequency.

TrkB (tropomyosin-related kinase B) controls the assembly and maintenance of GABAergic synapses in the cerebellar cortex.

Chen AI, Nguyen CN, Copenhagen DR, Badurek S, Minichiello L, Ranscht B, Reichardt LF.

J Neurosci 31(8):2769-2780, 2011.

In this work the authors investigated the role of TrkB in GABAergic inhibitory synapses in the mouse cerebellar cortex. Using a variety of techniques, including immunohistochemistry utilizing an mGluR2 antibody (Cat. #AB-N32), it was shown that TrkB is required for both assembly and maintenance of these synapses. The primary role of TrkB appears to be regulating the localization of synaptic constituents.

Molsidomine modulates the cNOS activity in an experimental model of cholinergic damage induced by 192-IgG saporin.

Hernandez-Melesio MA, Gonzalez-Esquivel D, Ortiz-Plata A, Sanchez-Mendoza A, Sanchez-Garcia A, Alcaraz-Zubeldia M, Rios C, Perez-Severiano F.

Neurosci Lett 491(2):133-137, 2011.

Nitric oxide (NO) is required for the survival of cholinergic neurons in the basal forebrain. Delivery of nerve growth factor (NGF) is related to the modulation of NO – as excessive NO can lead to excitotoxicity. The authors administered molsidomine to rats that had previously received 220 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum. Molsidomine is a NO donator, and produced a significant recovery of NO activity in lesioned animals, indicating a potential therapeutic pathway.

Histaminergic regulation of seasonal metabolic rhythms in Siberian hamsters.

I’anson H, Jethwa PH, Warner A, Ebling FJ.

Physiol Behav 103(3-4):268-278, 2011.

The role of central histaminergic mechanisms on seasonal catabolic state was investigated in hamsters. Siberian hamsters received bilateral 3.8-ng injections of orexin-SAP (Cat. #IT-20; discontinued) into the tuberomammillary posterior hypothalamic region. Saporin (Cat. #PR-01) was used as a control. During long days, lesioned animals displayed higher locomotor activity, greater oxygen intake, and no net weight gain. During shorter days (hibernation) with less activity, lesioned animals did not lose weight. The data indicate that histaminergic neurons are involved in body weight regulation.

Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics.

Leung LS, Petropoulos S, Shen B, Luo T, Herrick I, Rajakumar N, Ma J.

Exp Neurol 228(2):259-269, 2011.

Consciousness and response to general anesthesia have been linked to acetylcholine in the brain. The authors treated rats with 150-ng bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis to examine this connection. Lesioned animals were more affected by propofol and phenobarbitol than control animals. Some effects of halothane were also increased. The data indicate a role for acetylcholine in the brain in the response to general anesthesia.

PreBötzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression.

Montandon G, Qin W, Liu H, Ren J, Greer JJ, Horner RL.

J Neurosci 31(4):1292-1301, 2011.

In order to identify the neurons involved with respiratory depression due to administration of opioids, some neuro-transmission networks in the preBötzinger complex were locally manipulated. Among various techniques used to analyze the results was immunohistochemistry with anti-NK1r (Cat. #AB-N04, discontinued). Results show the preBötzinger complex is responsible for suppression of respiratory rate due to opioids.

Gene regulation in the rat prefrontal cortex after learning with or without cholinergic insult.

Paban V, Chambon C, Farioli F, Alescio-Lautier B.

Neurobiol Learn Mem 95(4)L441-452, 2011.

Microarray technology was used to screen gene expression in a model of attention and memory deficit. Rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum and nucleus basalis magnocellularis (37.5 ng per side and 75 ng per side respectively). Gene expression in memory loss following the lesion was defined by one cluster related to cytoskeleton organization and proliferation, and glial and vascular remodeling. These are processes associated with brain repair after injury.

Human monoclonal antibodies to sialyl-Lewisa (CA19.9) with potent CDC, ADCC, and antitumor activity.

Sawada R, Sun SM, Wu X, Hong F, Ragupathi G, Livingston PO, Scholz WW.

Clin Cancer Res 17(5):1024-1032, 2011.

In this work the authors investigated the use of a carbohydrate antigen, sialyl-Lewisa (CA19.9), as a target for cancer therapeutics. Human monoclonal antibodies were generated against CA19.9 and characterized using ELISA and flow cytometry. To assess internalization one antibody, 5B1, was combined with Hum-ZAP (Cat. #IT-22) and applied to CA19.9-expressing BxPC3 cells. The cytotoxicity of the 5B1-Hum-ZAP complex indicates that CA19.9 may be a target for cancer therapy.

Corticotropin-releasing factor critical for zebrafish camouflage behavior is regulated by light and sensitive to ethanol.

Wagle M, Mathur P, Guo S.

J Neurosci 31(1):214-224, 2011.

The authors used the hardwired camouflage response of zebrafish to explore neural circuit assembly and function. Corticotropin-releasing factor is a critical component of this pathway. Immunostaining, done with a CRF antibody (Cat. #AB-02) was part of the data that showed how both light exposure and ethanol affect the camouflage response. Understanding this system could provide a tool to further investigate the effect of alcohol on neural circuits.

Sézary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-ß on the cell surface.

Chung JS, Shiue LH, Duvic M, Pandya A, Cruz PDJ, Ariizumi K.

Blood 117(12):3382-3390, 2011.

Syndecan-4 (SD-4) is a transmembrane heparan sulfate proteoglycan. The Sézary syndrome (SS) subset of cutaneous T-cell lymphoma overexpresses distinct heparan sulfate moieties, giving the authors a specific target for these cells. Biotinylated DC-HIL-Fc (the extracelluar domain of dendritic cell-associated heparan sulfate proteoglycan-integrin ligand fused to Fc of mouse IgG) was combined at a 1:1 molar ratio with streptavidin-ZAP (Cat. #IT-27). In vitro, this targeted toxin eliminated SS cells, preventing their proliferation and suggesting a method for SS treatment.

Selective depletion of Mac-1-expressing microglia in rat subventricular zone does not alter neurogenic response early after stroke.

Heldmann U, Mine Y, Kokaia Z, Ekdahl CT, Lindvall O.

Exp Neurol 229(2):391-398, 2011.

One result of ischemic stroke is migration of newly formed neuroblasts into the injured area from the subventricular zone (SVZ). The authors investigated the role of microglia, which also accumulate in the SVZ after stroke, in this process. Rats received 5-µg or 10-µg intracerebroventricular injections of Mac-1-SAP (Cat. #IT-33) with varying schedules as to injection and sacrifice. The data indicate that the presence of microglia after stroke does not affect the number or migration of neuroblasts from the SVZ.

Brain stem catecholamines circuitry: Activation by alcohol and role in the hypothalamic-pituitary-adrenal response to this drug.

Lee S, Craddock Z, Rivier C.

J Neuroendocrinol 23(6):531-541, 2011.

In this work the authors investigated mechanisms underlying the stimulatory effect of alcohol on the hypothalamic-pituitary-adrenal axis (HPA). One method used was 33-ng injections of anti-DBH-SAP (Cat. #IT-03) into the A2/C2/C3 and A1/C1 regions. The data generated show that catecholamines, especially in the brainstem, regulate the HPA response to alcohol. This regulation utilizes α1-adrenergic receptors. Administration of anti-DBH-SAP to the A1-A2/C1-C3 regions disrupted the catecholaminergic input to the paraventricular nucleus.

Participation of hindbrain AMP-activated protein kinase in glucoprivic feeding.

Li AJ, Wang Q, Ritter S.

Diabetes 60(2):436-442, 2011.

Catecholamine neurons innervating the medial hypothalamus are involved in the control of glucoprivic feeding as well as other responses to glucose deficit. Rats received bilateral 82-ng injections of anti-DBH-SAP (Cat. #IT-03) into the paraventricular hypothalamic nucleus. Saporin (Cat. #PR-01) was used as a control. Lesioned animals did not respond to the administration of a competitive glucose inhibitor, nor did they display phosphorylation of pAMPKα, suggesting that AMPK may be part of a glucose-sensing mechanism.

The effects of intrathecal and systemic gabapentin on spinal substance p release.

Takasusuki T, Yaksh TL.

Anesth Analg 112(4):971-976, 2011.

Intrathecal or systemically-administered gabapentin is an antihyperalgesic. Given that gabapentin binds a voltage-sensitive calcium channel and that some of these channels regulate substance P (SP) release, the authors investigated whether gabapentin affects SP levels. Immunohistochemistry was done in rats following a gabapentin/formalin pain model. A neurokinin-1 receptor antibody (Cat. #AB-N04; discontinued) was used to quantitate NK1r, and therefore assess SP activity. It was found that both spinal and systemic gabapentin inhibit SP release from small, primary afferents.