targeted-toxins

Wiley RG, Kline IV RH, Vierck Jr CJ (2007) Anti-nociceptive effects of selectively destroying substance P receptor-expressing dorsal horn neurons using [Sar(9),Met(O(2))(11)]-substance P-saporin: Behavioral and anatomical analyses. Neuroscience 146:1333-1345. doi: 10.1016/j.neuroscience.2007.01.066

Summary: While lumbar injections of SP-SAP (Cat. #IT-07) produce specific lesions, use of this targeted conjugate in the forebrain has been problematic. The authors investigated the use of SSP-SAP (Cat. #IT-11), a conjugate of saporin with a stable analog of substance P. The greater stability of SSP-SAP resulted in increased potency as well as better specificity. SSP-SAP is shown to be a highly effective reagent for the removal of NK1 receptor-expressing neurons in the brain and spinal cord.

Related Products: SP-SAP (Cat. #IT-07), SSP-SAP (Cat. #IT-11)

Hanganu IL, Staiger JF, Ben-Ari Y, Khazipov R (2007) Cholinergic modulation of spindle bursts in the neonatal rat visual cortex in vivo. J Neurosci 27:5694-5705. doi: 10.1523/JNEUROSCI.5233-06.2007

Summary: The authors investigated the relationship between cholinergic drive and spindle burst oscillation driven by retinal waves. 0.5 µl of 0.2-µg/µl 192-IgG-SAP (Cat. #IT-01) was injected into both ventricles of rat pups. The lesioned animals displayed markedly decreased oscillatory activity. Since this activity may be used as a functional template for cortical networks and architecture, the results suggest a link between cholinergic activity and cortical development.

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

Domico LM, Cooper KR, Bernard LP, Zeevalk GD (2007) Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells. Neurotoxicology 28:1079-1091. doi: 10.1016/j.neuro.2007.04.008 PMID: 17597214

Summary: This work explores the mechanisms of neuronal damage associated with the ethylene-bis-dithiocarbamate fungicide mancozeb (MZ). In order to obtain a purified rat mesencephalic culture, the authors treated neuronal cultures with Mac-1-SAP (Cat. #IT-33) at a final concentration of 2 µg/ml. The microglia-free cultures did not display attenuated reactive oxygen species (ROS) production when treated with MZ. The data suggest that microglia are not required for ROS production in the presence of MZ.

Related Products: Mac-1-SAP rat (Cat. #IT-33), Antibody to Mac-1 (Cat. #AB-N06)

Schiltz JC, Sawchenko PE (2007) Specificity and generality of the involvement of catecholaminergic afferents in hypothalamic responses to immune insults. J Comp Neurol 502:455-467. doi: 10.1002/cne.21329

Summary: Interleukin-1 (IL-1) is one of the cytokines that mediates interactions between the immune system and the central nervous system. 380-ng injections of anti-DBH-SAP (Cat. #IT-03) were made into the paraventricular nucleus (PVH) of rats. Saporin (Cat. #PR-01) and mouse IgG-SAP (Cat. #IT-18) were used as controls. Lesioned animals demonstrated reduced responses to administration of IL-1, but restraint stress responses were left intact. The data suggest that ascending catecholaminergic projections mediate PVH response to IL-1.

Related Products: Anti-DBH-SAP (Cat. #IT-03), Saporin (Cat. #PR-01), Mouse IgG-SAP (Cat. #IT-18)

Myhrer T, Enger S, Aas P (2007) Anticonvulsant effects of damage to structures involved in seizure induction in rats exposed to soman. Neurotoxicology 28(4):819-828. doi: 10.1016/j.neuro.2007.03.010

Summary: Soman is a nerve agent that irreversibly inhibits acetylcholinesterase, resulting in respiratory dysfunction, seizures, convulsions, coma, and death. In this work the authors investigated whether elimination of cholinergic pathways in the medial septum (MS) or diagonal band nucleus (DBN) would affect the onset of convulsions. 0.3 µl of 0.5-µg/µl 192-IgG-SAP (Cat. #IT-01) was infused into the MS and/or DBN. Lesioned animals still experienced convulsions, suggesting that cholinergic MS systems are not the only ones involved.

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

Gibbs RB, Johnson DA (2007) Cholinergic lesions produce task-selective effects on delayed matching to position and configural association learning related to response pattern and strategy. Neurobiol Learn Mem 88:19-32. doi: 10.1016/j.nlm.2007.03.007

Summary: It has been well established that the cholinergic system of the basal forebrain plays a critical role in many cognitive processes. This work utilized injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum, the nucleus basalis magnocellularis, or both to examine the lesioning effect on two cognitive tasks in rats. The data indicate that cholinergic lesions of the basal forebrain produce learning deficits that are task specific, and that learning is affected without corresponding deficits in memory.

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

Aztiria E, Capodieci G, Arancio L, Leanza G (2007) Extensive training in a maze task reduces neurogenesis in the adult rat dentate gyrus probably as a result of stress. Neurosci Lett 416(2):133-137. doi: 10.1016/j.neulet.2007.01.069

Summary: Ascending cholinergic inputs from the basal forebrain modulate hippocampal neurogenesis, although it is not clear if the modulation is direct or indirect. In this study rats experienced extended training in a spatial navigation task following 192-IgG-SAP (Cat. #IT-01) lesions. 192-IgG-SAP was injected into the basal forebrain nuclei and the cerebellar cortex. Although the lesioned animals displayed an 80% reduction in neuron proliferation in the dentate gyrus, extended training and learning did not affect proliferation.

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

Q: Do conjugated toxins (dermorphin-saporin in particular) exhibit agonist effects? I’ve generated behavioral and tissue time course effects but have not established agonist effects for this conjugated toxin.

A: The peptide ligand toxins should exhibit agonist effects. They are constructed purposely to retain complete agonist activity, including for us the most important: internalization. So, for instance, SP-SAP (Cat. #IT-07) causes receptor internalization similar to SP, as reported in Mantyh et al.

As to dermorphin-SAP (Cat. #IT-12) specifically, it has agonist activity very much like dermorphin. This is reported in Porreca et al. in which it’s stated:

The bilateral microinjection of 3 pmol of dermorphin or of dermorphin-saporin directly into the RVM produced a robust antinociceptive effect in the 52°C hot-water tail-flick test. The peak antinociceptive effect of dermorphin, 78 ± 13.2% MPE, was not significantly different from that of the dermorphin-saporin conjugate, which was 59 ± 4.7% MPE (p > 0.5, Student’s t test).

Usually the amount needed to give a response is lower than the amount needed to kill a cell. Depending on what your system is; it may be a peculiarity of that system, but I would be a little concerned about not seeing an agonist effect. On the other hand, if you have demonstration of specific toxicity, it may not be all that crucial.

See: Targeted Toxins

Potts JT (2007) Featured Article: Nucleus tractus solitarii injections of substance P-conjugated saporin selectively disrupts baroflex-dependent pathways. Targeting Trends 8(2)

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

Read the featured article in Targeting Trends.

See Also:

• Potts JT et al. Targeted deletion of neurokinin-1 receptor expressing nucleus tractus solitarii neurons precludes somatosensory depression of arterial baroreceptor-heart rate reflex. Neuroscience 145(3):1168-1181, 2007.

Potts JT, Fong AY, Anguelov PI, Lee S, McGovern D, Grias I (2007) Targeted deletion of neurokinin-1 receptor expressing nucleus tractus solitarii neurons precludes somatosensory depression of arterial baroreceptor-heart rate reflex. Neuroscience 145(3):1168-1181. doi: 10.1016/j.neuroscience.2007.01.001

Summary: Previous work by these authors examined the role of substance P in arterial baroreflex. Here, 1.5 ng bilateral injections of SP-SAP (Cat. #IT-07) into the caudal nucleus tractus solitarii of rats were used to further elucidate the fundamental role of substance P in this system. The depressive effect of somatosensory input by neurokinin-1 receptor-expressing neurons on arterial baroreceptor-heart rate reflex was abolished in lesioned animals.

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

Read the featured article in Targeting Trends.