targeted-toxins

O’Sullivan JA, Youngblood BA, Schleimer RP, Bochner BS (2024) Siglecs as potential targets of therapy in human mast cell- and/or eosinophil-associated diseases. Semin Immunol 69:101799. doi: 10.1016/j.smim.2023.101799 PMID: 37413923

Objective: To review a subset of Siglecs and their various endogenous or synthetic sialoside ligands that regulate eosinophil and mast cell function and survival.

Summary: Sialic acid-binding immunoglobulin-like lectins (Siglecs) are vertebrate glycan-binding cell-surface proteins. Many Siglecs mediate cellular inhibitory activity and are of interest as part of a strategy to therapeutically lessen unwanted cellular responses. Human eosinophils and mast cells express overlapping but distinct patterns of Siglecs, and certain Siglecs have become the focus of novel therapies for allergic and other eosinophil and mast cell-related diseases.

Usage: Saporin in conjunction with CD22 glycomimetic ligand BPCNeuAc leads to cells death induction in a ligand-dependent manner on B-lymphoma cells (Collins et al.). Incubation with anti-Siglec-8 monoclonal antibody conjugated to saporin led to the death of malignant mast cells and eosinophils (O’Sullivan et al.)

Related Products: Saporin (Cat. #PR-01)

See Also:

• Collins BE, Blixt O, Han S, Duong B, Li H, Nathan JK, Bovin N, Paulson JC (2006) High-affinity ligand probes of CD22 overcome the threshold set by cis ligands to allow for binding, endocytosis, and killing of B cells. J Immunol 177(5):2994-3003. doi: 10.4049/jimmunol.177.5.2994 PMID: 16920935
• O’Sullivan J et al. Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol 141:1774-1785.e1777, 2018.

la Fleur SE, Blancas-Velazquez AS, Stenvers DJ, Kalsbeek A (2024) Circadian influences on feeding behavior. Nauropharmacology 256:110007. doi: 10.1016/j.neuropharm.2024.110007 PMID: 38795953

Objective: To review the effect of deletion of different clock genes on feeding behavior.

Summary: The most prominent effect on feeding behavior has been observed in Clock mutants, where as deletion of Bmal1 and Per1/2 only disrupts the day-night rhythm, but not overall intake. Damaging leptin-sensitive cells within the ARC using saporin-leptin injections (reducing the number of POMC and AgRP cells) induced a-rhythmicity in feeding behavior when animals were held either in a light-dark rhythm or continuous darkness, providing evidence that leptin-sensitive cells of the ARC are important for circadian feeding rhythmicity.

Related Products: Leptin-SAP (Cat. #IT-47)

See Also:

• Li AJ et al. Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms. Am J Physiol Regul Integr Comp Physiol 302(11):R1313-26, 2012.

Dai SP, Yang CC, Chin Y, Sun WH (2024) T cell death-associated gene 8-mediated distinct signaling pathways modulate the early and late phases of neuropathic pain. iScience 27(10):110955. doi: 10.1016/j.isci.2024.110955 PMID: 39381739

Objective: To elucidate how T cell death-associated gene 8 (TDAG8)-mediated signaling modulates neuron activities in a mouse model of chronic constriction injury-induced neuropathic pain.

Summary: TDAG8 participated alone in mechanical allodynia induced by constriction injury. TDAG8-Nav1.8 signaling in small-diameter isolectin B4-positive [IB4(+)] neurons initiate mechanical allodynia; it also modulated substance P release from IB4(-) neurons to facilitate the development of early mechanical allodynia. TDAG8-mediated signaling increased medium-to large-diameter IB4(-) neuron activity to maintain late mechanical allodynia; it also modulated substance P release in soma to reduce satellite glial number and Nav1.7 expression, thus attenuating chronic mechanical allodynia.

Usage: Mice were intrathecally injected with IB4-saporin (IB4-SAP, 0.06 mg/mL) or Saporin (0.06 mg/mL)

Related Products: IB4-SAP (Cat. #IT-10), Saporin (Cat. #PR-01)

Penna S, Zecchillo A, Di Verniere M, Fontana E, Iannello V, Palagano E, Mantero S, Cappelleri A, Rizzoli E, Santi L, Crisafulli L, Filibian M, Forlino A, Basso-Ricci L, Scala S, Scanziani E, Schinke T, Ficara F, Sobacchi C, Villa A, Capo V (2024) Correction of osteopetrosis in the neonate oc/oc murine model after lentiviral vector gene therapy and non-genotoxic conditioning. Front Endocrinol (Lausanne) 15:1450349. doi: 10.3389/fendo.2024.1450349 PMID: 39314524

Objective: To investigate whether gene therapy (GT) could minimize the immune-mediated complications of allogeneic hematopoietic stem cell transplantation (HSCT) and offer a prompt treatment.

Summary: Authors showed that lentiviral vector GT can revert the osteopetrotic bone phenotype, allowing long-term survival and reducing extramedullary haematopoiesis and that plerixafor-induced mobilization can further increase the high number of HSPCs circulating in peripheral blood, facilitating the collection of adequate numbers of cells for therapeutic purposes. Pre-transplant non-genotoxic conditioning allowed the stable engraftment of HSPCs, albeit at lower level than conventional total body irradiation, and led to long-term survival and correction of bone phenotype, in the absence of acute toxicity.

Usage: Recipient oc/oc mice were conditioned by CD45-SAP injections or total body irradiation (IRR)

Related Products: Anti-CD45.2-SAP (Cat. #IT-91)

Moschonas EH (2024) Cholinergic neurotransmission during performance of a sustained attention task after traumatic brain injury. Univ Pittsburgh School of Medicine Thesis.

Objective: To elucidate the role of basal forebrain cholinergic neurons (BFCNs) in mediating attentional performance and ACh efflux

Summary: Saporin-induced lesions to the nbM impaired signal detection accuracy during performance of the Sustained Attention Task (SAT). Similarly, in tasks of divided attention that involve both auditory and visual stimuli, cholinergic lesions to the nbM result in prolonged response times during bimodal trials compared to unimodal trials, which involve a single sensory modality.

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

See Also:

• McGaughy J et al. Sustained attention performance in rats with intracortical infusions of 192 IgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142. Behav Neurosci 112(6):1519-1525, 1998.
• McGaughy J et al. The role of cortical cholinergic afferent projections in cognition: impact of new selective immunotoxins. Behav Brain Res 115:251-263, 2000.
• Dalley JW et al. Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-Saporin-induced lesions of the medial prefrontal cortex. Cereb Cortex 14(8):922-932, 2004.
• Chudasama Y et al. Cholinergic modulation of visual attention and working memory: Dissociable effects of basal forebrain 192-IgG-saporin lesions and intraprefrontal infusions of scopolamine. Learn Mem 11(1):78-86, 2004.
• Botly LC et al. Cholinergic deafferentation of the neocortex using 192 IgG-saporin impairs feature binding in rats. J Neurosci 29:4120-4130, 2009.
• Butt AE et al. Impairments in negative patterning, but not simple discrimination learning, in rats with 192 IgG-Saporin lesions of the nucleus basalis magnocellularis. Behav Neurosci 116(2):241-255, 2002.
• Butt AE et al. Impairments in negative patterning, but not simple discrimination learning, in rats with 192 IgG-Saporin lesions of the nucleus basalis magnocellularis. Behav Neurosci 116(2):241-255, 2002.

Keilhoz A, Pathak I, Smith CL, Osman KL, Smith L, Oti G, Golzy M, Mz L, Lever TE, Nichols NL (2024) Tongue exercise ameliorates structural and functional upper airway deficits in a rodent model of hypoglossal motor neuron loss. Front Neurol 15:1441529. doi: 10.3389/fneur.2024.1441529 PMID: 39296960

Objective: To investigate the effects of a strength endurance tongue exercise program on upper airway structure and function.

Summary: Results showed that sham exercise-treated CTB-SAP rats have evidence of upper airway restriction (i.e., reduced airflow) and structural changes present in the upper airway (i.e., airway compression) when compared to rats treated with CTB-SAP and exercise and control rats with/without tongue exercise, which were ameliorated with tongue exercise. Additionally, CTB-SAP treated, sham exercise rats have evidence of increased lipid expression in the tongue consistent with previously observed tongue hypertrophy when compared to CTB-SAP treated exercise rats or control rats with/without tongue exercise.

Usage: Intralingual injection of either unconjugated CTB+SAP (20 μg CTB+25 μg SAP) or conjugated CTB-SAP (25 μg of CTB conjugated to SAP).

Related Products: CTB-SAP (Cat. #IT-14), Recombinant Cholera Toxin B (Cat. #PR-14), Saporin (Cat. #PR-01)

Kostenko A, Prezzavento O, de Leo G, D’Arco D, Gulion R, Caccamo A, Leanza G (2024) Cognitive and histopathological alterations in rat models of early- and late-phase memory dysfunction: Effects of sigma-1 receptor activation. J Alzheimers Dis 101(3):797-811. doi: 10.3233/JAD-240618 PMID: 39240642

Objective: This study sought to assess the role of (±)-cyclopropane carboxylate (PPCC) on working memory deficits caused by noradrenergic depletion.

Summary: While (±)-PPCC alone at a dose of 1 mg/kg/day failed to affect working memory in lesioned animals, its association with the α2 adrenergic receptor agonist clonidine, completely blocked noradrenaline release, significantly improving rat performance. This effect, distinct from noradrenaline activity, is likely to result from a direct action of the (±)-PPCC compound onto sigma-1 receptors, as pre-treatment with the selective sigma-1 receptor antagonist BD-1047 reversed the improved working memory performance. Despite such clear functional effects, the treatment did not affect noradrenergic neuron survival or terminal fiber proliferation.

Usage: Bilateral intraventricular injections of anti-DBH-saporin (IT-03). Either 1.25μg or 2.5μg of the immunotoxin was dissolved in 7μl of sterile PBS and administered into each lateral ventricle (resulting in a total of 2.5μg or 5.0μg per rat in a 7 + 7μl volume of vehicle).

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

Runyon K, Bui T, Mazanek S, Hartle A, Marschalko K, Howe WM (2024) Distinct cholinergic circuits underlie discrete effects of reward on attention. Front Mol Neurosci. Front Mol Neurosci 17:1429316. doi: 10.3389/fnmol.2024.1429316 PMID: 39268248

Objective: Review the basic neuroanatomy of attention, reward, and cholinergic systems.

Summary: Authors examined specific contexts in which attention and reward computations interact. They proposed two discrete neural circuits whereby acetylcholine, released from cell groups located in different parts of the brain, mediates the impact of stimulus-reward associations as well as motivation on attentional control. Authors concluded by examining these circuits as a potential shared loci of dysfunction across diseases states associated with deficits in attention and reward.

Usage: Lesions of basal forebrain via ACh-immunotoxin 192-IgG-SAP (IT-01) impaired performance on a sustained attention task designed for rodents, selectively reducing the capacity of rats to report the presence of instructive cues, while having no effect on their ability to report the absence of these cues0

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

See Also:

• McGaughy J et al. Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density. Behav Neurosci 110:247-265, 1996.

Huo C, Lombardi F, Blanco-Centurion C, Shiromani PJ, Ivanov PC (2024) Role of the locus coeruleus arousal promoting neurons in maintaining brain criticality across the sleep-wake cycle. J Neurosci 44(35):e1939232024. doi: 10.1523/JNEUROSCI.1939-23.2024 PMID: 38951035

Objective: To investigate dynamics of θ- and δ-bursts during the sleep-wake cycle of rats with lesion in the wake-promoting locus coeruleus (LC).

Summary: The findings indicate that critical dynamics of θ- and δ-bursts arise from a balanced interplay of LC and ventrolateral preoptic nucleus (VLPO), which maintains brain tuning to criticality across the sleep-wake cycle.

Usage: To confirm the efficacy of anti-DBH-SAP (IT-03) to kill noradrenergic-LC neurons and their fibers. 192 IgG-SAP (IT-01) was selected as an additional control because like anti-DBH-SAP it is a conjugate of a monoclonal antibody and saporin. Bilateral microinjection of 192-IgG-SAP and Anti-DBH-SAP were used at a volume of 0.3μL at a rate of 0.1μL/5 min using a pressure injector

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

Konofal E (2024) From past to future: 50 years of pharmacological interventions to treat narcolepsy. Pharmacol Biochem Behav 241:173804. doi: 10.1016/j.pbb.2024.173804 PMID: 38852786

Objective: This review article discusses the historical progression and transformative insights that have characterized the treatment of narcolepsy from its initial documentation to the present day.

Summary: The research continues to push the boundaries of what is known about this complex sleep disorder, the hope for treatments that can fundamentally alter the disease trajectory becomes increasingly tangible. This paradigm shift towards addressing the autoimmune, neuroinflammatory, and neurodegenerative aspects of narcolepsy promises to revolutionize patient care.

Usage: See also these references using Orexin-B-SAP (IT-20) to create a narcoleptic-like rat model via LH lesions.

See Also:

• Gerashchenko D et al. Hypocretin-2-saporin lesions of the lateral hypothalamus produce narcoleptic-like sleep behavior in the rat. J Neurosci 21(18):7273-7283, 2001.
• Gerashchenko K et al. Effects of lateral hypothalamic lesion with the neurotoxin hypocretin-2-saporin on sleep in Long-Evans rats. Neuroscience 116:223-235, 2003.