targeted-toxins

Gil-Bea FJ, Dominguez J, Garcia-Alloza M, Marcos B, Lasheras B, Ramirez MJ (2004) Facilitation of cholinergic transmission by combined treatment of ondansetron with flumazenil after cortical cholinergic deafferentation. Neuropharmacology 47(2):225-232. doi: 10.1016/j.neuropharm.2004.03.014

Summary: Previous studies from this group demonstrated that 5-HT(3) receptor antagonists potentiated by GABA(A) antagonists increased acetylcholine (ACh) release in the rat cerebral cortex. This series of experiments investigated the effects of these antagonists on rats with 0.067 µg-bilateral infusions of 192-Saporin (Cat. #IT-01) into the nucleus basalis magnocellularis. Even after lesioning with 192-Saporin, rats treated with the 5-HT(3) and GABA(A) receptor antagonists displayed increased ACh release, indicating that these antagonists may have use as treatments for cognitive disorders.

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

Q: What dosage of 192-Saporin (192-IgG-SAP, Cat. #IT-01) should be used in the lateral ventricle to eliminate cholinergic neurons in the basal forebrain, including substantia innominata (SI)? I read that Calza et al [1] used 2 or 3 micrograms/4.5 µl and found this was highly effective.

A: It has been our experience that two- or three-micrograms into the lateral ventricle is necessary to obtain a maximum cholinergic basal forebrain (CBF) lesion. However, these doses typically kill some cerebellar Purkinje cells. Another issue is that some cholinergic neurons in the NBM region are never killed by 192-Saporin.

Q: Should we expect to be able to kill all or almost all ChAT SI neurons?

A: Mesulam’s lab has some data [2,3] to suggest that these neurons innervate the amygdala and adjacent cortex. Generally lesions of the septum and diagonal band are complete, but when you get more caudal, i.e. SI region, there will be some cholinergic neurons left. When you do ChAT or AChE stains, the amygdala and adjacent cortex are not denervated whereas the hippocampus, olfactory system and all the rest of the cortex are devoid of cholinergic terminals.

Q: Is there another toxin that will eliminate the remaining ChAT SI neurons?

A: There may be other targeted conjugates that could clean out the residual cells in the SI region if we knew what markers they co-express. For example, our SSP-saporin (Cat. #IT-11) conjugate is very good at removing cells that express the NK-1 receptor such as striatal cholinergic interneurons.

See: 192-IgG-SAP (Cat. #IT-01), SSP-SAP (Cat. #IT-11), Targeted Toxins

References

1. Calza L et al. Neural stem cells and cholinergic neurons: Regulation by immunolesion and treatment with mitogens, retinoic acid, and nerve growth factor. Proc Natl Acad Sci U S A 100(12):7325-7330, 2003.
2. Heckers S et al. Two types of cholinergic projections to the rat amygdala. Neuroscience 60:383-397, 1994.
3. Heckers S et al. Complete and selective cholinergic denervation of rat neocortex and hippocampus but not amygdala by an immunotoxin against the p75 NGF receptor. J Neurosci 14:1271-1289, 1994.

Nishiguchi J, Sasaki K, Seki S, Chancellor MB, Erickson KA, de Groat WC, Kumon H, Yoshimura N (2004) Effects of isolectin B4-conjugated saporin, a targeting cytotoxin, on bladder overactivity induced by bladder irritation. Eur J Neurosci 20(2):474-482. doi: 10.1111/j.1460-9568.2004.03508.x

Summary: It has been demonstrated that IB4-binding non-peptidergic C-fiber neuronal populations are present in afferent pathways to the bladder. The authors used intrathecal administration of 8 µl of 2.5 µM IB4-SAP (Cat. #IT-10) to investigate what roles these neurons play in bladder function. Treated animals displayed a reduction of IB4 afferent nerve terminal staining, as well as a suppression of bladder overactivity due to bladder irritation, without a change in normal bladder function.

Related Products: IB4-SAP (Cat. #IT-10)

Read the featured article in Targeting Trends.

Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC (2004) Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 19(12):3305-3316. doi: 10.1111/j.0953-816X.2004.03439.x

Summary: In Alzheimer’s disease basal cholinergic degeneration is accompanied by glial activation and the release of pro-inflammatory cytokines. To investigate whether neural events other than degeneration can cause effects of Alzheimer’s disease, the authors treated mice with minocycline after lesioning the basal forebrain with 3.6 µg of mu p75-SAP (Cat. #IT-16). Administration of minocycline reduced the loss of cholinergic neurons, reduced glial response to the lesion, and lessened the cognitive impairment due to mu p75-SAP lesions.

Related Products: mu p75-SAP (Cat. #IT-16)

Fargo KN, Sengelaub DR (2004) Exogenous testosterone prevents motoneuron atrophy induced by contralateral motoneuron depletion. J Neurobiol 60(3):348-359. doi: 10.1002/neu.20027

Summary: Gonadal steroids have been shown to supply a variety of neuroprotective and neurotherapeutic effects. Using 1-µl injections of 0.1% CTB-SAP (Cat. #IT-14) into the ipsalateral bulbocavernosus and the levator ani of rats, the authors examined the protective effects of testosterone on motoneuron morphology. After the lesion was induced some rats were castrated, and all animals were treated with exogenous testosterone. The results suggest that high-normal levels of testosterone can prevent motoneuron atrophy induced by contralateral motoneuron depletion.

Related Products: CTB-SAP (Cat. #IT-14)

Cooper-Kuhn CM, Winkler J, Kuhn HG (2004) Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res 77(2):155-165. doi: 10.1002/jnr.20116

Summary: Adult mammalian brains can produce new neurons, mainly in two areas: the interconnected system of the lateral ventricle and the olfactory bulb, and the dentate gyrus of the hippocampus. The authors used a 3.5 µg-injection of 192-Saporin (Cat. #IT-01) into the right ventricle of rats to determine whether cholinergic input is necessary for adult neurogenesis. The results suggest that acetylcholine, a product of cholinergic neurons, is necessary for the survival of newly-formed neurons.

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

Winters BD, Dunnett SB (2004) Selective lesioning of the cholinergic septo-hippocampal pathway does not disrupt spatial short-term memory: a comparison with the effects of fimbria-fornix lesions. Behav Neurosci 118(3):546-562. doi: 10.1037/0735-7044.118.3.546

Summary: The authors wished to investigate the role of the cholinergic system of the basal forebrain in delayed matching (DMTP)- and nonmatching (DNMTP)-to-position tasks after bilateral injections of 0.035 µg of 192-Saporin (Cat. #IT-01) into the dorsal and ventral hippocampus. The treated animals were compared to rats given fimbria-fornix (FF) lesions. Only the FF-lesioned animals showed impairment on DMTP and DNMTP tasks, demonstrating that the cholinergic septohippocampal system is not required for successful DMTP or DNMTP performance.

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

Lappi DA, Wiley RG (2004) Immunotoxins and neuropeptide-toxin conjugates experimental applications. Mini Rev Med Chem 4(5):585-595. doi: 10.2174/1389557043403882

Summary: The use of targeted toxins in research is rich and varied; here the authors describe some of the exciting results that researchers have made in the neurosciences.

Blanco-Centurion C, Gerashchenko D, Salin-Pascual RJ, Shiromani PJ (2004) Effects of hypocretin2-saporin and antidopamine-beta-hydroxylase-saporin neurotoxic lesions of the dorsolateral pons on sleep and muscle tone. Eur J Neurosci 19(10):2741-2752. doi: 10.1111/j.0953-816X.2004.03366.x

Summary: Narcolepsy is linked to the loss of orexin (or hypocretin)-containing neurons in the brain. These neurons are located in the perifornical region of the posterior hypothalamus and innervate the locus coeruleus (LC). To investigate the role of the LC in sleep the authors injected 0.3 µl of 192-Saporin (Cat. IT-01) or anti-DBH-SAP (Cat. #IT-03) at 1 µg/µl. They also used 0.3 µl of orexin-SAP (Cat. #IT-20) at either 90 ng/µl or 60 ng/µl in a separate group of animals. The results indicate that orexin innervation to the pons plays a role in arousal from sleep.

Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-DBH-SAP (Cat. #IT-03), Orexin-B-SAP (Cat. #IT-20)

Li AJ, Ritter S (2004) Glucoprivation increases expression of neuropeptide Y mRNA in hindbrain neurons that innervate the hypothalamus. Eur J Neurosci 19(8):2147-2154. doi: 10.1111/j.1460-9568.2004.03287.x

Summary: It is suspected that hypothalamic neuropeptide Y (NPY) innvervation of the hypothalamus contributes to glucoregulatory feeding. Along with mRNA studies, the authors injected 42 ng of anti-DBH-SAP (Cat. #IT-03) into the paraventricular nucleus. Elimination of the hindbrain catecholamine/NPY neurons abolished increases in NPY expression due to glucoprivic conditions. This response suggests that NPY hindbrain neurons play a role in glucoprivic feeding and other glucoregulatory responses.

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