targeted-toxins

Shivakumar AB, Mehak SF, Gupta A, Gangadharan G (2024) Medial septal cholinergic neurotransmission is essential for social memory in mice. Prog Neuropsychopharmacol Biol Psychiatry 136:111207. doi: 10.1016/j.pnpbp.2024.111207 PMID: 39615870

Objective: To identify the physiological link between medial septal dependent cholinergic theta oscillations in the hippocampus and social memory behavior.

Summary: Selective ablation of cholinergic neurons in the medial septum (MS) impaired social memory in mice, while their sociability and social novelty remained intact. Additionally, these mice showed an attenuation of cholinergic theta oscillations (3–7Hz) in the hippocampal dorsal CA2 (dCA2) region. Furthermore, enhancing dCA2 theta oscillations by elevating cholinergic signaling using acetylcholinesterase inhibitor rescued social memory deficit. Together, these results indicate that 1) medial septal cholinergic neurons are essential for modulating social memory and 2) cholinergic hippocampal theta oscillations contribute to social memory processes.

Usage: Ablation of cholinergic neurons in the MS using mu-p75-SAP (IT-16, 0.2μg/0.5μl).

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

Morishata Y, Fuentes I, Gonzalez-Salinas S, Favate J, Mejaes J, Zushida K, Nishi A, Hevi C, Goldsmith N, Buyske S, Sillivan SE, Miller CA, Kandel ER, Uchida S, Shah P, Alarcon JM, Barker DJ, Shumyatsky GP (2024) Dopamine release and dopamine-related gene expression in the amygdala are modulated by the gastrin-releasing peptide in opposite directions during stress-enhanced fear learning and extinction. Molexular Psychiatry doi: 10.1038/s41380-024-02843-8 PMID: 39580604

Objective: To investigate neural circuits serving the dopamine function for fear extinction and PTSD.

Summary: Results demonstrate that gastrin-releasing peptide regulates dopamine function in stress-enhanced fear processing and identifies Grp as the first gene known to regulate dopaminergic control of fear extinction.

Usage: Bombesin-SAP (IT-40) or Blank-SAP (IT-21) (80 ng/µl) dissolved in saline were injected bilaterally into the basolateral amygdala (AP: -2.0 mm, ML: ±3.25 mm, DV: -4.3 mm) in 0.3 µl volume.

Related Products: Bombesin-SAP (Cat. #IT-40), Blank-SAP (Cat. #IT-21)

Kato K, Serizawa R, Yokoyama T, Nakamuta N, Yamamoto Y (2024) Fos expression in A1/C1 neurons of rats exposed to hypoxia, hypercapnia, or hypercapnic hypoxia. Neurosci Lett 843:138024. doi: 10.1016/j.neulet.2024.138024

Objective: To compare the distribution of Fos expression in catecholaminergic neurons with immunoreactivity for dopamine-β-hydroxylase (DBH) of the ventrolateral medulla exposed to hypoxia (10%O2), hypercapnia(8%CO2), and hypercapnic hypoxia (8%CO2and10%O2)

Summary: The number of double-immunoreactive neurons in hypercapnic hypoxia-exposed rats was comparable to that in the control group. The present results suggest that adrenergic C1 neurons are specifically activated by hypoxia and are involved in the regulation of respiratory and circulatory functions.

Usage: A previous study reported that cardiorespiratory responses to hypoxic exposure (8%O2), such as hyperventilation and tachycardia, disappeared after the injury of C1 neurons by an injection of the immunotoxin anti-DBH-saporin into the rostral ventrolateral medulla of rats.

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

See Also:

• Malheiros-Lima M et al. Depletion of rostral ventrolateral medullary catecholaminergic neurons impairs the hypoxic ventilatory response in conscious rats. Neuroscience 351:1-14, 2017.

Ammar AO (2024) Involvement of peptidergic Edinger-Westphal nucleus in the neurobiology of migraine and acute alcohol exposure. Univ Pecs Thesis.

Objective: To confirm the role of Edinger-Westphal nucleus/urocortin1 (EWcp/UCN1) neurons in migraine. They hypothesized that selective ablation of EWcp/UCN1 neurons will influence the migraine-related behaviors induced by CGRP.

Summary: Upon selective ablation of EWcp/UCN1 neurons, authors examined the migraine-related behaviors in response to calcitonin gene-related peptide (CGRP) treatment. Leptin-SAP treatment significantly reduced the number of UCN1 immunoreactive neurons in the EWcp compared to naïve mice. Before ablation of EWcp/UCN1 neurons, CGRP treatment significantly reduced the periorbital withdrawal threshold compared to saline.

Usage: For selective UCN1 neuron ablation, 50 nl of Leptin-SAP was microinjected into the rostral and caudal parts of the EWcp area.

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

Schaible HG, König C, Ebersberger A (2024) Spinal pain processing in arthritis: Neuron and glia (inter)actions. J Neurochem 168(11):3644-3662. doi: 10.1111/jnc.15742 PMID: 36520021

Objective: To address the mechanisms of spinal sensitization evoked by arthritis.

Summary: Neutralization of spinal cytokines by intrathecal interventions attenuates mechanical hyperalgesia. This effect may in part result from local suppression of spinal sensitization and in part from efferent effects which attenuate the inflammatory process in the joint. In summary, arthritis evokes significant spinal hyperexcitability which is likely to contribute to the phenotype of arthritis pain in patients

Usage: Selective microglia destruction with the immunotoxin saporin conjugated to Mac1 antibody (Mac-1-SAP Cat #IT-06, recognizes Mac1 receptor on microglia) attenuated the development of hyperalgesia.

Related Products: Mac-1-SAP mouse/human (Cat. #IT-06)

Kuroda M, Komatsu N, Kosai A, Hamakubo T, Abe T (2024) Anti-EGFR antibody immunotoxins improve cytotoxic effects in the salivary gland cancer A253 cell line. doi: 10.1016/j.ajoms.2024.11.003

Objective: To confirm the antitumor effects of IT-Cetuximab (IT-Cmab= saporin-conjugated anti-EGFR antibody), which is cetuximab conjugated with a toxin, targeting salivary gland cancers—a type of cancer with limited effective treatment options aside from surgery.

Summary: Cmab alone exhibited no cytotoxic effects, but IT-Cmab demonstrated concentration-dependent cytotoxic effects in A253 cells.

Usage: Cytotoxicity assay (@1.34pM to 4.2nM)

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

Lin CCJ, Tian Y, Tanzi RE, Jorfi M (2024) Approaches for studying neuroimmune interactions in Alzheimer’s disease. Trends Immunol S1471-4906(24)00248-5. doi: 10.1016/j.it.2024.10.002 PMID: 39537528

Objective: To examine cutting-edge strategies – encompassing animal and cellular models – used to investigate the roles of peripheral immune cells in AD.

Summary: Recent studies using rodent models and innovative human-based cellular systems are beginning to shed light on how peripheral immune cells infiltrate the brain and modulate disease progression.

Usage: Strategies for bone marrow depletion using anti-CD45 or anti-CD117 antibodies conjugated with the ribosome-inactivating protein saporin have been used.

Related Products: Anti-CD117-SAP (Cat. #IT-83), Anti-CD45.2-SAP (Cat. #IT-91)

See Also:

• Palchaudhuri R et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol 34:738-745, 2016.
• Czechowicz A et al. Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation. Nat Commun 10:617, 2019.

Moreno-Rodríguez M, Martínez-Gardeazabal J, Bengoetxea de Tena I, Llorente-Ovejero A, Lombardero L, González de San Román E, Giménez-Llort L, Manuel I, Rodríguez-Puertas R (2024) Cognitive improvement via cortical cannabinoid receptors and choline-containing lipids. Br J Pharmacol doi: 10.1111/bph.17381 PMID: 39489624

Objective: Authors hypothesized that activation of the endocannabinoid system may confer neuroprotection against cholinergic degeneration.

Summary: Degeneration, induced by 192-IgG-saporin, of baso-cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). The cannabinoid agonist WIN55,212-2 restored cortical cholinergic transmission and LPC levels via activation of cannabinoid receptors. This activation altered cortical lipid homeostasis mainly by reducing sphingomyelins in lesioned animals. These modifications were crucial for memory recovery.

Usage: Basal forebrain cholinergic degeneration was induced following bilateral stereotaxic injection of 192IgG-saporin (130 ng/μl, IT-01) into the nucleus basalis magnocellularis (NBM).

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

Chuang KH, Zhou XA, Xia Y, Li z, Qian L, Eeles E, Ngiam G, Fripp J, Coulson EJ (2024) Cholinergic basal forebrain neurons regulate vascular dynamics and cerebrospinal fluid flux. bioRxiv 2024.08.25.609536. doi: 10.1101/2024.08.25.609536

Objective: To show that vascular-CSF coupling correlates with cortical cholinergic activity in non-demented aged humans.

Summary: Waste from the brain is cleared via a cerebrospinal fluid (CSF) exchange pathway. Problems in this pathway is suggested to underlie the pathogenesis of many brain conditions. Cerebrovascula oscillation that couples with pulsatile CSF inflow is suggested to drive the flow of fluid, however how this coupling is regulated in unlcear. The resultsfor the study suggest a neurovascular mechanism by which CSF/glymphatic flux is modulated by cholinergic neuronal activity, thereby providing a conceptual basis for the development of diagnostics and treatments for glymphatic dysfunction.

Usage: Injections of mu-p75-SAP (0.5 mg/ml, IT-16) or control Rabbit-IgG-SAP (0.5 mg/ml, IT-35) were performed into the border between the medial septum and ventral diagonal band. In the first study, the toxin was infused at a rate of 0.4 μl/min (1.5μl total volume), which resulted in a large amount of ablation. In the second study, the toxin concentration was reduced to 0.3 mg/ml to preserve more cholinergic neurons and was infused at a rate of 0.18μl/min (1.0μl total volume).

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Blanco T, Nakagawa H, Musayeva A, Krauthammer M, Singh RB, Narimatsu A, Ge H, Shoushtari SI, Dana R (2024) Acquired immunostimulatory phenotype of migratory CD103+ DCs promotes alloimmunity following corneal transplantation. JCI Insight 9(20):e182469. doi: 10.1172/jci.insight.182469 PMID: 39235864

Objective: To investigate the interaction between antigen-presenting cell subsets, specifically CD11b+ dendritic cells (DC2) and CD103+ dendritic cells (DC1),in the context of transplant immunity.

Summary: The findings highlight the critical role of CD103+ DC1 in modulating host alloimmune responses. In recipients with uninflamed corneal beds, migratory CD103+ DC1 exhibit a tolerogenic phenotype. These cells influence the immunogenic behavior of CD11b+ DC2 primarily through IL-10 production, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and promoting Treg-mediated tolerance through αvβ8 integrin–activated TGF-β1. Together, these mechanisms contribute to improved graft survival.

Usage: In vivo depletion of CD103+ DC1: Recipient BALB/c or RAG-/- mice were administered 2.0 mg/kg of Anti-CD103-SAP (IT-50) intraperitoneally, or an equivalent dose of control conjugate (IgG-SAP).

Related Products: Anti-CD103-SAP (Cat. #IT-50), Rat IgG-SAP (Cat. #IT-17)