2014 Targeting Trends Review

Grupe M, Paolone G, Jensen AA, Sandager-Nielsen K, Sarter M, Grunnet M (2013) Selective potentiation of (alpha4)3(beta2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats. Biochem Pharmacol 86(10):1487-1496. doi: 10.1016/j.bcp.2013.09.005

Summary: Nicotinic acetylcholine receptors (nAChR) are involved in a wide range of processes in the central nervous system, many having to do with higher cognitive functions. In order to better understand how these receptors mediate attentional performance, the authors investigated glutamate release under varying conditions. In one series of experiments rats received a 160-ng injection of 192-IgG-SAP (Cat. #IT-01) into the right medial prefrontal cortex. The resulting decrease in glutamate release after the cholinergic lesion adds to the data indicating that positive modulation of nAChR may help alleviate attentional impairments caused by some brain disorders.

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

Romano A, Potes CS, Tempesta B, Cassano T, Cuomo V, Lutz T, Gaetani S (2013) Hindbrain noradrenergic input to the hypothalamic PVN mediates the activation of oxytocinergic neurons induced by the satiety factor oleoylethanolamide. Am J Physiol Endocrinol Metab 305(10):E1266-73. doi: 10.1152/ajpendo.00411.2013

Summary: Feeding behavior and energy balance are in part controlled by signals from the gut. Oleoylethanolamide (OEA) is an acylethanolamide that is thought to play a role in this network. Since peripheral administration of OEA has effects on the nucleus of the solitary tract (NTS) and paraventricular nucleus (PVN) the authors investigated the role of noradrenergic afferent input to these areas. Rats received bilateral 84-ng injections of Anti-DBH-SAP (Cat. #IT-03) into the PVN. Mouse IgG-SAP (Cat. #IT-18) was used as a control.

Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)

Hayashida K (2013) Substance P-saporin for bone cancer pain in dogs: Can man’s best friend solve the lost in translation problem in analgesic development?. Anesthesiology 119(5):999-1000. doi: 10.1097/ALN.0b013e3182a951a2

Summary: This editorial describes the SP-SAP papers in this latest issue of Anesthesiology. The results of the paper are discussed, and the potential in using companion dogs for pain models is emphasized. While most pain models have been rodent-based, companion dogs provide models for chronic pain due to natural causes such as cancer and arthritis, along with frequent opportunity for behavioral assessments by the owner. Such assessments can be done without stress to the animal.

Related Products: SP-SAP (Cat. #IT-07)

See Also:

• Wiese AJ et al. Intrathecal substance p-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. Anesthesiology 119(5):1163-1177, 2013.
• Brown DC et al. Intrathecal substance p-saporin in the dog: efficacy in bone cancer pain. Anesthesiology 119(5):1178-1185, 2013.

Wiese AJ, Rathbun M, Butt MT, Malkmus SA, Richter PJ, Osborn KG, Xu Q, Veesart SL, Steinauer JJ, Higgins D, Lappi DA, Russell B, Yaksh TL (2013) Intrathecal substance p-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. Anesthesiology 119(5):1163-1177. doi: 10.1097/ALN.0b013e3182a95164

Summary: Here the authors investigate the safety parameters of SP-SAP on purpose-bred beagles (currently in human clinical trials). The dogs received 1.5, 15, or 150 μg intrathecal injections of the conjugate. SP-SAP pharmacology and physiological effects were assessed by behavioral and functional observations, immunohistochemistry, ELISA, blood and urine analysis, histopathology, and in situ hybridization. The general conclusions include that neurokinin-1 receptor (NK1r) positive neuron loss is detectable as soon as 7 days after administration of SP-SAP, the neuron loss is permanent, toxicity is specific to NK1r-positive neurons, and, other than the 150 μg dose, NK1r neuron loss was restricted to the superficial dorsal horn.

Related Products: SP-SAP (Cat. #IT-07), SP-SAP (Cat. #IT-07)

Read the featured article in Targeting Trends.

Brown DC, Agnello K (2013) Intrathecal substance p-saporin in the dog: efficacy in bone cancer pain. Anesthesiology 119(5):1178-1185. doi: 10.1097/ALN.0b013e3182a95188

Summary: This work demonstrates the use of naturally occurring bone cancer in dogs as a model for pain therapy. Companion dogs with bone cancer received 20-60 μg intrathecal injections of SP-SAP (currently in human clinical trials) depending on the size of the dog. Significantly more dogs in the control group required unblinding and adjustment of pain care than in the SP-SAP group, indicating the efficacy of SP-SAP in pain control. This study also demonstrates the validity of the dog model for testing analgesic protocols.

Related Products: SP-SAP (Cat. #IT-07)

Read the featured article in Targeting Trends.

Cutuli D, De Bartolo P, Caporali P, Tartaglione AM, Oddi D, D’Amato FR, Nobili A, D’Amelio M, Petrosini L (2013) Neuroprotective effects of donepezil against cholinergic depletion. Alzheimers Res Ther 5(5):50. doi: 10.1186/alzrt215

Summary: Acetylcholinesterase inhibitors appear to be one of the only pharmacological tools available to reduce cognitive deficits caused by the loss of cholinergic neurons in the basal forebrain. Here the authors pre-treated rats with the aceytlcholinesterase inhibitor donepezil before administering 0.5 μg of 192-IgG-SAP (Cat. #IT-01) into each side of the medial septum. Analysis of working memory, spatial discrimination, social novelty preference, and ultrasonic localizations, along with measuring hippocampal and neocortical caspase-3 activity indicates that donepezil pre-treatment ameliorates some effects of the cholinergic depletion.

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

Hess SM, Young EF, Miller KR, Vincent BG, Buntzman AS, Collins EJ, Frelinger JA, Hess PR (2013) Deletion of naive T cells recognizing the minor histocompatibility antigen HY with toxin-coupled peptide-MHC class I tetramers inhibits cognate CTL responses and alters immunodominance. Transpl Immunol 29(1-4):138-145. doi: 10.1016/j.trim.2013.10.005

Summary: The authors utilized biotinylated peptide-MHC class I tetramers with Streptavidin-ZAP (Cat. #IT-27) to selectively delete a specific population of alloreactive T cells in mice. Animals received iv 33-pmol injections of the toxic tetramer, and the data indicate that these toxic tetramers can prevent the induction of donor-specific responses that result in organ rejection.

Related Products: Streptavidin-ZAP (Cat. #IT-27)

Kucinski A, Paolone G, Bradshaw M, Albin RL, Sarter M (2013) Modeling fall propensity in Parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci 33(42):16522-16539. doi: 10.1523/JNEUROSCI.2545-13.2013

Summary: Parkinson’s disease produces a range of symptoms, some of which are unresponsive to therapies such as levodopa. These nonmotor symptoms include cognitive impairments and deficiencies in gait and balance. Here the authors develop a system to assess fall propensity in rats and examine the interaction between loss of cortical cholinergic and striatal dopaminergic afferents. Rats received 160-ng injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis and substantia innominata of the basal forebrain. The results indicate that the dual lesions result in diminished striatal control of complex movement.

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

Parent MJ, Cyr M, Aliaga A, Kostikov A, Schirrmacher E, Soucy JP, Mechawar N, Rosa-Neto P, Bedard MA (2013) Concordance between in vivo and postmortem measurements of cholinergic denervation in rats using PET with [18F]FEOBV and choline acetyltransferase immunochemistry. EJNMMI Res 3(1):70. doi: 10.1186/2191-219X-3-70

Summary: Positron emission tomography (PET) imaging agents have been developed for the quantitative evaluation of cholinergic systems in vivo, and in this work the authors examine the concordance between the in vivo use of PET and post-mortem analysis of cholinergic damage. Rats received unilateral 0.2-0.25 μg injections of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis. Animals were scanned using [18F]fluoroethoxybenzovesamicol, then sacrificed for cholineacetyltransferase immunohistochemistry. The results support the use of PET as an in vivo method for analyzing the loss of cholinergic neurons.

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

Baxter MG, Bucci DJ, Gorman LK, Wiley RG, Gallagher M (2013) Reprint: Selective immunotoxic lesions of basal forebrain cholinergic cells: Effects on learning and memory in rats. Behav Neurosci 127(5):619-627 . doi: 10.1037/a0033939

Summary: In this reprint of a 1995 article, 192-IgG-SAP (Cat. #IT-01) was used to separate the depletion of cortical cholineacetyltransferase and behavioral impairment – which had previously been linked by research using less specific lesioning methods. Since the original 1995 publication, hundreds of papers have been published using a variety of lesioning techniques and a wide range of ATS products.

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

See Also:

• Baxter MG et al. Selective immunotoxic lesions of basal forebrain cholinergic cells: effects on learning and memory in rats. Behav Neurosci 109:714-722, 1995.