targeted-toxins

Traissard N, Herbeaux K, Cosquer B, Jeltsch H, Ferry B, Galani R, Pernon A, Majchrzak M, Cassel JC (2007) Combined damage to entorhinal cortex and cholinergic basal forebrain neurons, two early neurodegenerative features accompanying Alzheimer’s Disease: Effects on locomotor activity and memory functions in rats. Neuropsychopharmacology 32(4):851-871. doi: 10.1038/sj.npp.1301116

Summary: Two characteristics of Alzheimer’s disease (AD) are cholinergic dysfunction in the basal forebrain, and neuronal damage in the entorhinal cortex. Using 5 µg intracerebroventricular (icv) injections of 192-IgG-SAP (Cat. #IT-01), and 2.3 µg icv injections of OX7-SAP (Cat. #IT-02), locomotor activity, working, and reference memory of rats were examined. Although 192-IgG-SAP lesions caused limited deficits, rats receiving both lesions exhibited several behaviors associated with AD. The authors suggest that combining these lesions may be a more accurate model for AD than 192-IgG-SAP alone.

Related Products: 192-IgG-SAP (Cat. #IT-01), OX7-SAP (Cat. #IT-02)

Vera-Portocarrero LP, Yie JX, Kowal J, Ossipov MH, King T, Porreca F (2006) Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis. Gastroenterology 130(7):2155-2164. doi: 10.1053/j.gastro.2006.03.025

Summary: Here the authors investigated the role of ascending or descending pathways in the mediation of pain caused by pancreatitis. Rats received 1.5 pmol injections of dermorphin-SAP (Cat. #IT-12) into each side of the rostral ventromedial medulla. Abdominal hypersensitivity was tested using von Frey filaments. Although the ablation of mu-opioid receptor-expressing neurons by dermorphin-SAP did not prevent the initial expression of pancreatitis pain, maintenance of this pain was absent. The data link maintenance of pancreatitis pain to descending pathways.

Related Products: Dermorphin-SAP / MOR-SAP (Cat. #IT-12)

Basbaum AI, Julius D (2006) Toward better pain control. Sci Am 294(6):60-67. doi: 10.1038/scientificamerican0606-60

Summary: The authors discuss some of the advances in understanding and treating different types of pain, and specifically outline circuits, receptors, and ligands involved in pain pathways. Several treatments are described, one of which is the use of SP-SAP (Cat. #IT-07) to disrupt the chronic pain pathway in the spinal cord.

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

Grimaldi P, Rossi F (2006) Lack of neurogenesis in the adult rat cerebellum after Purkinje cell degeneration and growth factor infusion. Eur J Neurosci 23(10):2657-2668. doi: 10.1111/j.1460-9568.2006.04803.x

Summary: Although neurogenesis occurs in very specific areas of the mammalian brain, neural progenitors can be found in many central nervous system sites. Here the authors examined neurogenesis in the rat cerebellum. 2.2 µg of 192-IgG-SAP (Cat. #IT-01) was injected into each lateral ventricle, and some animals were given exogenous EGF, bFGF, or FGF8. In this model, the local environment was not sufficient to direct neuronal differentiation, even with the addition of growth factors.

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

Lu J, Sherman D, Devor M, Saper CB (2006) A putative flip-flop switch for control of REM sleep. Nature 441(1):589-594. doi: 10.1038/nature04767

Summary: The authors propose a REM sleep regulatory system that involves GABAergic and glutaminergic neurons in the mesopontine tegmentum. Among other work, 2 µl of 0.1% orexin-SAP (Cat. #IT-20) was injected into the medial medullary reticular formation of rats. This work suggests the sharp transitions into and out of REM sleep are controlled by reciprocal interactions between GABAergic REM-off and REM-on neuronal populations.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Dinh TT, Flynn FW, Ritter S (2006) Hypotensive hypovolemia and hypoglycemia activate different hindbrain catecholamine neurons with projections to the hypothalamus. Am J Physiol Regul Integr Comp Physiol 291(4):R870-R879. doi: 10.1152/ajpregu.00094.2006

Summary: Hypovolemia, a decrease in blood plasma volume, results in secretion of arginine vasopressin (AVP). This work investigates the role of hindbrain catecholamine neurons in hypovolemia-induced AVP secretion. Rats were treated with bilateral 42 ng injections of anti-DBH-SAP (Cat. #IT-03) into the paraventricular nucleus of the hypothalamus, and hypovolemia was induced by blood withdrawal. Treated animals displayed severely impaired AVP response, as well as lower food intake and corticosterone secretion in response to insulin.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Madden CJ, Stocker SD, Sved AF (2006) Attenuation of homeostatic responses to hypotension and glucoprivation after destruction of catecholaminergic rostral ventrolateral medulla (RVLM) neurons. Am J Physiol Regul Integr Comp Physiol 291(3):R751-R759. doi: 10.1152/ajpregu.00800.2005

Summary: C1 neurons in the RVLM express dopamine-beta-hydroxylase (DBH). Anti-DBH-SAP (Cat. #IT-03) was used to eliminate these neurons and examine cardiovascular homeostasis in response to a physiological challenge such as hypotension. 21 ng of anti-DBH-SAP was injected into the RVLM of rats. After food and water had been removed from the cage, the lesioned animals were treated with hydralazine to reduce blood pressure. The results demonstrate that RVLM-C1 cells are involved in responses to homeostatic challenges.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Fitz NF, Gibbs RB, Johnson DA (2006) Aversive stimulus attenuates impairment of acquisition in a delayed match to position T-maze task caused by a selective lesion of septo-hippocampal cholinergic projections. Brain Res Bull 69(6):660-665. doi: 10.1016/j.brainresbull.2006.03.011

Summary: It is known that infusion of 192-IgG-SAP (Cat. #IT-01) into the medial septum of rats impairs acquisition of a delayed matching to position (DMP) T-maze task. Here, the authors evaluated whether introduction of an aversive stimulus 30 minutes prior to training would attenuate this deficit. Treated rats received 0.22 µg of 192-IgG-SAP injected into the medial septum. Data indicate that treated rats receiving an intraperitoneal injection of saline 30 minutes prior to training displayed less impairment than rats not receiving the aversive stimulus.

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

Li AJ, Wang Q, Ritter S (2006) Differential responsiveness of dopamine-beta-hydroxylase gene expression to glucoprivation in different catecholamine cell groups. Endocrinology 147(7):3428-3434. doi: 10.1210/en.2006-0235

Summary: This work examines how subpopulations of hindbrain catecholaminergic neurons participate in systemic glucoregulation. Rats were treated with bilateral 42 ng infusions of anti-DBH-SAP (Cat. #IT-03) into the paraventricular nucleus of the hypothalamus. Dopamine-beta-hydroxylase (DBH) expression in glucoprivic animals was then analyzed by in situ hybridization and immunohistochemistry. The data demonstrate that the ventrolateral medulla contains most of the catecholamine neurons responsive to glucoprivation.

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

Q: I spoke with someone from your technical service over the phone and got the impression that your product dermorphin-SAP (Cat. #IT-12) is not a retrograde and will only affect the terminals or the cells that express mu opioid receptors in the injection site in the brain. I have three questions:

1) Do you have any written document on this issue?

A: That the peptide-toxins don’t undergo retrograde transport is an example of negative data, so people haven’t really been publishing too much on that. But two articles deal specifically with it: Lappi and Wiley[1] and Bugarith et al.[2] The latter, in particular, presents solid data on the inability of the peptide ligand toxin NPY-SAP (Cat. #IT-28) to undergo retrograde transport. I don’t think we have a single example of a peptide-ligand toxin that undergoes retrograde transport. In order for a peptide-toxin to kill cells, the cell body must have the receptor and the toxin must be injected within reach of the cell body. We’ve made a mistake in not putting that in the data sheets, and will begin to change that.

2) Will dermorphin-SAP also kill terminals in the injection site or just cell bodies?

A: Let me cite for you: Tokuno et al., Efferent projections from the striatal patch compartment: anterograde degeneration after selective ablation of neurons expressing mu-opioid receptor in rats.[3] As the title implies, they address the issue of elimination of processes following cell body destruction.

3) If it also kills terminals, will it affect their remote cell bodies?

A: I’m not sure I understand this question, but that won’t stop me from trying to answer it: The situation is the contrary, because the destruction of processes comes from the action taking place in the cell body. Our experience is that once the cell body is gone, it’s just a matter of time for the process to go away. This makes these toxins a little different than others. In fact, we recommend that you wait two weeks at least to see immunohistological evidence of a toxic effect after injection of a saporin toxin in vivo. That’s how long it takes the removal process to get rid of all the antigens that you might want to use for evidence of cell loss.

Q: Can I inject NPY-SAP to destroy projections through retrograde transport?

A: Regarding NPY-SAP, a peptide-toxin, see previous response. The antibody-toxins such as 192-IgG-SAP (Cat. #IT-01) or anti-DBH-SAP (Cat. #IT-03) will undergo retrograde transport from terminals to cell bodies. Thus, you can put 192-IgG-SAP into the cortex and it will destroy neurons in the basal forebrain, because the saporin (probably the whole conjugate) is transported from the projection to the cell body. Likewise, anti-DBH-SAP in the spinal cord destroyed hindbrain catecholaminergic neurons by retrograde transport.[4] All the antibody-toxins appear to undergo retrograde transport. 

Finally, the lectin-toxins, CTB-SAP (Cat. #IT-14) and IB4-SAP (Cat. #IT-10) undergo retrograde transport, just like the native lectins do. CTB-SAP is well-described in Llewellyn-Smith et al.[5] and several others. For IB4-SAP, Vulchanova et al.[6] describe use, along with several other articles on our reference page. In addition, detailed discussions are available in the book Molecular Neurosurgery with Targeted Toxins,[7] available from Humana Press.

See: Targeted Toxins

References

1. Lappi DA et al. Entering through the doors of perception: characterization of a highly selective Substance P receptor-targeted toxin. Neuropeptides 34(5):323-328, 2000.
2. Bugarith K et al. Basomedial hypothalamic injections of neuropeptide Y conjugated to saporin selectively disrupt hypothalamic controls of food intake. Endocrinology 146(3):1179-1191, 2005.
3. Tokuno H et al. Efferent projections from the striatal patch compartment: anterograde degeneration after selective ablation of neurons expressing mu-opioid receptor in rats. Neurosci Lett 332(1):5-8, 2002.
4. Ritter S et al. Immunotoxic destruction of distinct catecholamine subgroups produces selective impairment of glucoregulatory responses and neuronal activation. J Comp Neurol 432(2):197-216, 2001.
5. Llewellyn-Smith IJ et al. Retrogradely transported CTB-saporin kills sympathetic preganglionic neurons. Neuroreport 10(2):307-312, 1999.
6. Vulchanova L et al. Cytotoxic targeting of isolectin IB4-binding sensory neurons. Neuroscience 108(1):143-155, 2001.
7. Wiley RG et al. Molecular neurosurgery with targeted toxins. , 2005. Humana Press, Totowa, New Jersey