targeted-toxins

Harris RBS (2023) Low dose peripheral leptin infusion produces selective activation of ventromedial hypothalamic and hindbrain STAT3. Am J Physiol Endocrinol Metab 325(1):E72-E82. doi: 10.1152/ajpendo.00083.2023 PMID: 37285599

Objective: To show that the deletion of leptin-receptor expressing cells in the ventromedial hypothalamus (VMH) has no effect on basal body weight or body fat mass, but greatly attenuates the inhibition of food intake.

Summary: This study evaluates leptin’s impact on hypothalamic pSTAT3 in leptin-infused versus injected rats. High-dose leptin suppressed food intake and reduced weight and fat mass without affecting energy metrics, with pSTAT3 increases observed in the VMH only during intake suppression and in the nucleus of the solitary tract over both short and extended periods. These results highlight the role of VMH and hindbrain receptors in mediating leptin’s effects on food intake and metabolic changes.

Usage: Leptin-SAP is referenced in Seamon et al 2019: Male Sprague-Dawley rats received bilateral VMH 75 nl injections of 260 ng/microliter of Leptin-SAP (IT-47) or Blank-Saporin (IT-21).

Related Products: Leptin-SAP (Cat. #IT-47), Blank-SAP (Cat. #IT-21)

See Also:

• Seamon M et al. Leptin receptor-expressing neurons in ventromedial nucleus of the hypothalamus contribute to weight loss caused by fourth ventricle leptin infusions. Am J Physiol Endocrinol Metab 317(4):E586-E596, 2019.

Keilholz A, Homan C, Schroeder A, Osman K, Smith C, Pathak I, Streeter K, Ozden I, Ma L, Lever T, Nichols N (2023) Tongue exercise-induced functional and structural upper airway plasticity in a rodent model of hypoglossal (XII) motor neuron loss. American Physiology Summit 2023 Meeting Abstracts 38(S1)

Objective: Examine if upper airway function/coordination can be improved in lower motor neuron (LMN) degeneration by tongue exercise-induced axis plasticity.

Summary: Tongue muscle weakness in patients with motor neuron diseases suggests a potential role for therapeutic exercise but lacks evidence due to lack of an appropriate model. Data suggests that tongue exercise in CTB-SAP rats results in enhanced XII motor plasticity and mitigates structural airway changes. In conclusion, tongue exercise appears to cause XII-tongue axis plasticity to improve upper airway function and coordination in the face of XII LMN degeneration.

Usage: The authors developed a novel rodent model using intralingual injections of CTB-SAP to induce targeted loss of XII motor neurons and motor output.

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

Holborough-Kerkvliet MD, Kroos S, van de Wetering R, Toes REM (2023) Addressing the key issue: Antigen-specific targeting of B cells in autoimmune diseases. Immunol Lett 259:37-45. doi: 10.1016/j.imlet.2023.05.005 PMID: 37209914

Objective: Using cyclic citrullinated peptide (CCP) conjugated to CNBz and saporin to eliminate autoreactive B cells, as a treatment for rheumatoid arthritis (RA).

Summary: Joint damage in the body creates cyclic citrullinated peptide (CCP) which is a marker of Rheumatoid arthritis (RA). The CCP active site that autoantibodies target is blocked with CNBz and the whole complex is conjugated with saporin allowing cytotoxicity directed towards autoreactive B cells, a damaging element of RA, without being reactive with CCP-targeted autoantibodies.

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

See Also:

• Lelieveldt LPWM et al. Sequential prodrug strategy to target and eliminate ACPA-selective autoreactive B cells. Mol Pharm 15(12):5565-5573, 2018.

Chen CH, Tsai TC, Wu YJ, Hsu KS (2023) Gastric vagal afferent signaling to the basolateral amygdala mediates anxiety-like behaviors in experimental colitis mice. JCI Insight e161874. doi: 10.1172/jci.insight.161874 PMID: 37200091

Objective: This study aimed to characterize gut-to-brain signaling and brain circuitry responsible for anxiety-like behaviors in a mouse model of inflammatory bowel disease.

Summary: The researchers found that mice with experimental colitis induced by dextran sulfate sodium administration displayed increased anxiety-like behaviors, which were prevented by cutting the vagus nerve connecting the gut to the brain. Further experiments showed that silencing brain cells in the locus coeruleus that project to the basolateral amygdala reduced anxiety behaviors in the colitis mice.

Usage: CCK-SAP (250 ng/µl) or Blank-SAP (250 ng/µl) were unilaterally or bilaterally injected to rostral (0.5 µl) and caudal (0.5 µl) parts of the nodose ganglia using a beveled injection pipette controlled by a microprocessor-controlled injector at the speed of 50 nl/sec.

Related Products: CCK-SAP (Cat. #IT-31), Blank-SAP (Cat. #IT-21)

Choi P (2023) The VLM a1/c1 ca/npy neuronal projections to the perifornical area of the lateral hypothalamus and its functional role in glucoprivic feeding. Washington State Univ Thesis.

Objective: This dissertation aimed to determine the role of neuropeptide Y (NPY) receptor signaling from the ventrolateral medulla (VLM) catecholamine (CA) neurons in the lateral hypothalamus (LHA) for glucoprivic feeding.

Summary: The results showed that NPY receptor-expressing neurons in the perifornical area of the LHA are required for glucoprivic feeding evoked by 2-deoxyglucose. Furthermore, antagonism of NPY Y1 or Y2 receptors in the LHA attenuated feeding evoked by chemogenetic activation of VLM CA neurons, indicating NPY release from VLM neurons activates LHA NPY receptors to elicit glucoprivic feeding.

Usage: NPY-SAP (50 ng per 100 nL/site) or control Blank-SAP (50 ng per 100 nL/site) dissolved in 0.01 M phosphate buffer was infused slowly over a 5 minute period directly into the perifornical lateral hypothalamic (stereotaxic coordinate: 2.8 mm caudal from bregma, +/- 1.2 mm lateral to the midline, and -7.4 mm from the dura mater) through a pulled glass capillary pipette (30 µm tip diameter) connected to a Picospritzer. The rats were allowed at least 7 days for a full recovery from surgery and NPY-SAP-induced neuronal ablation.

Related Products: NPY-SAP (Cat. #IT-28), Blank-SAP (Cat. #IT-21)

Sainz AE (2023) The effects of loss of orexin neurons on attention. William & Mary Thesis.

Objective: This paper examines the effects of loss of orexin neurons on attention in mice.

Summary: This undergraduate honors thesis from William & Mary tested attention in mice after selective loss of orexin neurons, which are important for arousal. The researchers found impairments in sustained attention and cognitive flexibility in the mice missing orexin neurons.

Usage: 0.5 µl of Orexin-B-SAP (0.4 µg/µl) or saline was administered to both sides of the lateral hypothalamus for 30 seconds using a 1 µl syringe.

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

Zhou Y, Zhang K, Wang F, Chen J, Chen S, Wu M, Lai M, Zhang Y, Zhou W (2023) Polypyrimidine tract binding protein knockdown reverses depression-like behaviors and cognition impairment in mice with lesioned cholinergic neurons. Front Aging Neurosci 15:1174341. doi: 10.3389/fnagi.2023.1174341 PMID: 37181622

Objective: Examine the mechanisms of how knockdown of the RNA-binding protein polypyrimidine tract binding protein (PTB) reverses depression-like behavior and cognition impairment in mice with lesioned cholinergic neurons.

Summary: A specific loss of cholinergic neurons in the horizontal limb of the diagonal band of broca (HDB) is correlated with depression and dysfunction of cognition in mice. The authors induced cholinergic neuron loss via injection of 192-IgG-SAP. This was followed by injection of either antisense oligonucleotides or adeno-associated virus-shRNA in the injured area of HDB to knockdown PTB. Knockdown of PTB by these two approaches was found to relieve depression-like behaviors and alleviate cognitive impairment and the findings suggest that supplementing cholinergic neurons after PTB knockdown may be a therapeutic approach to reverse depression-like behaviors and cognitive impairment.

Usage: 192 IgG-saporin (Cat. IT-01) was injected bilaterally into the HDB at a volume of 0.25 μl with a concentration of 1 μg/μL, per side.

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

Chen LQ, Lv XJ, Guo QH, Lv SS, Lv N, Xu WD, Yu J, Zhang YQ (2023) Asymmetric activation of microglia in the hippocampus drives anxiodepressive consequences of trigeminal neuralgia in rodents. Br J Pharmacol 180(8):1090-1113. doi: 10.1111/bph.15994 PMID: 36443951

Objective: To determine whether and how microglia are involved in trigeminal neuralgia-induced anxiodepression.

Summary: Findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviors via IL-1β. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia-induced anxiety and depression was uncovered.

Usage: Mac-1–SAP (IT-06, 2.5 μg/1 μl, per side) was bilaterally injected into the hippocampal CA1 area on Day 0 and Day 7 after constriction of the infraorbital nerve, respectively. Unconjugated saporin was used as a control.

Related Products: Saporin (Cat. #PR-01), Mac-1-SAP mouse/human (Cat. #IT-06)

Yaksh TL, dos Santo G, Lemes J, Malange K (2023) Neuraxial drug delivery in pain management: An overview of past, present, and future. Anaesthesiology 37(2):243-265. doi: 10.1016/j.bpa.2023.04.003 PMID: 37321769

Objective: Review of neuraxial therapeutic delivery platforms for pain management and the regulation caused by pharmacological targeting of dorsal root ganglion and dorsal horn systems.

Summary: Studies have shown modulation by spinal opiates, but subsequent work reveals the complexity of the neuraxial system. Various delivery platforms, such as viral transfection, antisense and targeted neurotoxins give evidence to approaches to selectively address the acute and chronic pain phenotype. Substance P-Saporin is discussed as a method to lesion NK1R-containing neurons for the treatment of chronic pain.

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

See Also:

• Wiese AJ et al. Intrathecal substance p-saporin in the dog: distribution, safety, and spinal neurokinin-1 receptor ablation. Anesthesiology 119(5):1163-1177, 2013.
• Brown DC et al. Intrathecal substance p-saporin in the dog: efficacy in bone cancer pain. Anesthesiology 119(5):1178-1185, 2013.
• Wiley RG Substance P receptor-expressing dorsal horn neurons: Lessons from the targeted cytotoxin, substance P-saporin. Pain 136:7-10, 2008.

Wu D, Yu N, Gao Y, Xiong R, Liu L, Lei H, Jin S, Liu J, Liu Y, Xie J, Liu E, Zhou Q, Liu Y, Li S, Wei L, Lv J, Yu H, Zeng W, Zhou Q, Xu F, Luo MH, Zhang Y, Yang Y, Wang JZ (2023) Targeting a vulnerable septum-hippocampus cholinergic circuit in a critical time window ameliorates tau-impaired memory consolidation. Mol Neurodegener 18(1):23. doi: 10.1186/s13024-023-00614-7 PMID: 37060096

Objective: There is an urgent need to study the targeting strategy for the MS-hippocampus cholinergic pathway to rescue tau-impaired memory.

Summary: Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer’s disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. The authors found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm dependent manner. 192-IgG-Saporin was used to create an Alzheimer’s Disease animal model.

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

See Also:

• Dornan WA et al. Comparison of site-specific injections into the basal forebrain on water maze and radial arm maze performance in the male rat after immunolesioning with 192 IgG saporin. Behav Brain Res 82:93-101, 1996.