targeted-toxins

Dinh TT, Duffy P, Ritter S (2002) Immunotoxin lesion of spinally projecting catecholamine neurons impairs the adrenal medullary response to glucoprivation and the sympathetic response to forced swim. Neuroscience 2002 Abstracts 76.5. Society for Neuroscience, Orlando, FL.

Summary: Distinct populations of hindbrain catecholamine neurons project spinally to innervate sympathetic and adrenal medullary preganglionic neurons. Previously we injected the immunotoxin, saporin conjugated to anti-dopamine beta hydroxylase (DSAP), into the spinal cord to selectively lesion these neurons. DSAP lesions abolished adrenal medullary Fos expression following insulin-induced hypoglycemia or 2-deoxy-D-glucose (2DG) and eliminated the hyperglycemic response to 2DG, which is mediated by adrenal medullary epinephrine (E) secretion. Here we examine the plasma E and norepinephrine (NE) responses to 2DG (250 mg/kg, s.c.) and to 5 min of forced swim in rats injected at T2-T4 with DSAP or unconjugated saporin (SAP) control solution. Blood was sampled remotely via jugular catheters between 0 and 240 min after 2DG or swim. Immunohistochemistry confirmed loss of dopamine B-hydroxylase throughout the spinal cord of DSAP rats. In DSAPs, both plasma E and hyperglycemic responses to 2DG were abolished or severely impaired compared to SAPs. 2DG did not elevate plasma NE in either group. Swim stress increased NE in both SAPs and DSAPs, but the DSAP response was only 60% of the SAP response. Results show for the first time that the selective activation of the adrenal medulla by glucoprivation, described previously, is mediated by spinally projecting catecholamine neurons. Results also demonstrate that spinal catecholamine terminals, presumeably arising from different hindbrain neurons, contribute to, but are not entirely responsible for, sympathetic neuronal responses to swim stress.

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

Varga C, Grosche J, Brauer K, Seeger J, Harkany T, Hartig W (2002) Cholinergic neurons in the rabbit forebrain: Chemoarchitecture, in vivo labeling, immunolesions. Neuroscience 2002 Abstracts 35.3. Society for Neuroscience, Orlando, FL.

Summary: While the rabbit basal forebrain and its cholinergic components became useful targets for modeling of neuropathological changes associated with Alzheimer’s disease, their neuroanatomical organization is still largely elusive. Hence, we focused on (i) the number of cholinergic basal forebrain neurons (CBFN)in the major nuclei based on choline acetyltransferase (ChAT) immunoperoxidase labeling, (ii) the density of ChAT-immunoreactive fibers in distinct neocortical and hippocampal areas, (iii) mapping of projecting CBFN by low-affinity neurotrophin receptor p75 (p75NTR ) staining and (iv) the double fluorescence labeling of ChAT and the neuronal markers p75NTR, nitric oxide synthase (NOS), calbindin, calretinin, parvalbumin, tyrosine hydroxylase and substance P. While cholinergic interneurons were found in the hippocampus, they were not detectable in the neocortex. CBFN were shown to abundantly co-express p75NTR, except in the substantia innominata and ventral pallidum. Whereas cholinergic neurons were devoid of most investigated markers, a subset also contained calbindin or NOS. The selective in vivo labeling of CBFN was achieved with intracerebroventricularly (i.c.v.) injected carbocyanine 3-conjugated ME20.4IgG that recognizes an extracellular epitope of p75NTR. Parallel experiments revealed that the i.c.v. injection of ME20.4IgG-saporin conjugates led to the specific immunolesion of cholinergic cells in about one week, whereas long-term effects of the immunotoxin remain to be further elucidated.

Related Products: ME20.4-SAP (Cat. #IT-15)

Turchi JN, Saunders RC, Mishkin M (2002) Effects of cholinergic deafferentation of rhinal cortex on visual recognition in monkeys. Neuroscience 2002 Abstracts 82.5. Society for Neuroscience, Orlando, FL.

Summary: Excitotoxic lesions of the rhinal (perirhinal/entorhinal) cortices yield substantial deficits in visual recognition (Baxter and Murray, 2001; Malkova et al., 2001). To evaluate the mnemonic role of cholinergic inputs to this region, we compared the visual recognition performance of untreated monkeys with that of monkeys given rhinal cortex infusions of the selective cholinergic immunotoxin ME20.4-SAP. This toxin binds to the p75 receptor, borne by corticopetal cholinergic neurons of the basal forebrain, and is retrogradely transported to the cell body where it permanently destroys ribosomal function. Both groups were first trained to criterion in the rule for delayed nonmatching-to-sample (DNMS) with trial-unique stimuli at a 10-s delay in a Wisconsin General Testing Apparatus. This was followed by treatment and recovery for the experimental group (n=3) and an equivalent rest period for the control group (n=4), after which both groups were retrained on the DNMS rule and then given a memory performance test with increasing delays (30, 60, and 120 s) and list lengths (3, 5, 10, and 20 stimuli). The experimental group relearned the DNMS rule without significant impairment but then demonstrated robust deficits when tested with increasing delays (a mean of 83% vs 95% for controls) and list lengths (67% vs 86% for controls). The findings complement results obtained in a study of muscarinic receptor blockade in the perirhinal cortex (Tang et al., 1997) and indicate that cholinergic integrity of the rhinal cortex is critical for visual recognition memory.

Related Products: ME20.4-SAP (Cat. #IT-15)

Mohapel P, Leanza G, Lindvall O (2002) Alterations in forebrain acetylcholine influence hippocampal neurogenesis in the adult rodent. Neuroscience 2002 Abstracts 23.9. Society for Neuroscience, Orlando, FL.

Summary: Little is known about how various experiential, environmental and pathological factors regulate neurogenesis in the adult hippocampus. Since the hippocampus receives abundant cholinergic innervation and contains some of the densest distributions of acetylcholine (ACh) fibers, we investigated its potential role in adult neurogenesis. Adult rats received multiple bromodeoxyuridine (BrdU) injections 3 weeks following lesions of the adult rodent forebrain cholinergic projections by intracerebroventricular infusions of 192 IgG-saporin. The day following BrdU administration we observed a significant 20% to 30 % decrease in proliferation in the subgranular cell layer of the dentate gyrus with ACh lesioning. This decrease persisted through to 4 weeks after BrdU administration, when most proliferated cells co-expressed neuronal markers. Conversely, in a separate experiment, naive rats receiving simultaneous injections of the ACh agonist physostigmine and BrdU demonstrated a 30 % increase in proliferated cells (1 day later) and neurons (4 weeks later) in the subgranular cell layer. Our data indicate that cholinergic mechanisms in the forebrain are involved in the regulation of neurogenesis and that this effect may be indirect or direct in the hippocampus.

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

Suzuki R, Morcuende S, Webber M, Hunt SP, Dickenson AH (2002) Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways. Nat Neurosci 5(12):1319-1326. doi: 10.1038/nn966

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

Tokuno H, Chiken S, Kametani K, Moriizumi T (2002) 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. doi: 10.1016/s0304-3940(02)00837-6

Summary: Taking advantage of the fact that neurons in patch compartments of the striatum express µ-opioid receptors, the authors injected 8.5 ng of dermorphin-SAP (Cat. #IT-12) into the striatum of rats. This lesion produced a degeneration of patch neurons as well as anterograde degeneration of efferent fibers from patch compartments, allowing further elucidation of the functional organization of the striatum.

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

Bechade C, Mallecourt C, Sedel F, Vyas S, Triller A (2002) Motoneuron-derived neurotrophin-3 is a survival factor for PAX2-expressing spinal interneurons. J Neurosci 22(20):8779-8784. doi: 10.1523/JNEUROSCI.22-20-08779.2002

Summary: In the rat, half of motoneurons die between embryonic day 15 and postnatal day 1. Programmed cell death of interneurons is not as well characterized. The authors cultured explants of brachial neural tubes from rat embryos in the presence of 200 ng/ml of 192-Saporin (Cat. #IT-01). Although 192-Saporin had no direct effect on interneurons in culture, elimination of p75-neurotrophin receptor-expressing neurons caused the interneurons to die.

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

Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA (2002) Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci 22(20):9086-9098. doi: 10.1523/JNEUROSCI.22-20-09086.2002

Summary: Using 5 x 10-5 M intrathecal injections of SP-SAP (Cat. #IT-07) the authors examined the role of SPR-expressing neurons in modulation of pain and hyperalgesia. Treated animals exhibited highly attenuated sensitization to stimuli after capsaicin treatment as compared to controls, but normal responses in the absence of capsaicin

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

Cassel JC (2002) Featured Article: Does 192-IgG-Saporin or 5,7-DHT kill cognitive functions in the rat?. Targeting Trends 3(4)

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

Read the featured article in Targeting Trends.

See Also:

• Lehmann O et al. 5,7-DHT-induced hippocampal 5-HT depletion attenuates behavioural deficits produced by 192 IgG-saporin lesions of septal cholinergic neurons in the rat. Eur J Neurosci 15(12):1991-2006, 2002.
• Lehmann O et al. Combined 192 IgG-saporin and 5,7-dihydroxytryptamine lesions in the male rat brain: A neurochemical and behavioral study. Pharmacol Biochem Behav 72(4):899-912, 2002.
• Galani R et al. Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats. Physiol Behav 76:75-90, 2002.

Zeitschel U, Schliebs R, Rossner S, Bigl V, Eschrich K, Bigl M (2002) Changes in activity and expression of phosphofructokinase in different rat brain regions after basal forebrain cholinergic lesion. J Neurochem 83(2):371-380. doi: 10.1046/j.1471-4159.2002.01127.x

Summary: The authors used intraventricular injections of 4 µg of 192-Saporin (Cat. #IT-01) in rats to investigate whether impaired cholinergic transmission may cause metabolic changes. Although the results demonstrate an initial increase in a cortical glucose metabolic marker, this increase was transient. The authors conclude that cholinergic systems do not control cortical glucose metabolic mechanisms affected by Alzheimer’s disease.

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