targeted-toxins

Souza GMPR, Abbott SBG (2024) Loss-of-function of chemoreceptor neurons in the retrotrapezoid nucleus: What have we learned from it?. Respir Physiol Neurobiol 322:104217. doi: 10.1016/j.resp.2024.104217 PMID: 38237884

Objective: To discuss the current definition of chemoreceptor neurons in the retrotrapezoid nucleus (RTN) and describe how this definition has evolved over time.

Summary: Studies offer evidence that RTN neurons are indispensable for the central respiratory chemoreflex in mammals and exert a tonic drive to breathe at rest. Moreover, RTN has an interdependent relationship with oxygen sensing mechanisms for the maintenance of the neural drive to breathe and blood gas homeostasis. Collectively, RTN neurons are a genetically-defined group of putative central respiratory chemoreceptors that generate CO2-dependent drive that supports eupneic breathing and stimulates the hypercapnic ventilatory reflex.

Usage: One widely adopted approach to eliminate RTN neurons utilizes local microinjections of the ribosomal-toxin Saporin conjugated to the analogue of substance-P (SSP-SAP),which results in cell death of neurokinin receptor 1-expressing neurons in a concentration-dependent manner.

Related Products: SSP-SAP (Cat. #IT-11)

See Also:

• Nattie EE et al. Substance P-saporin lesion of neurons with NK1 receptors in one chemoreceptor site in rats decreases ventilation and chemosensitivity. J Physiol 544(Pt 2):603-616, 2002.
• Souza GMPR et al. Breathing regulation and blood gas homeostasis after near complete lesions of the retrotrapezoid nucleus in adult rats. J Physiol 596(13):2521-2545, 2018.
• Takakura AC et al. Phox2b-expressing retrotrapezoid neurons and the integration of central and peripheral chemosensory control of breathing in conscious rats. Exp Physiol 99(3):571-585, 2014.
• Takakura AC et al. Selective lesion of retrotrapezoid Phox2b-expressing neurons raises the apneic threshold in rats. J Physiol 586:2975-2991, 2008.

Aerts EG (2024) Estradiol’s role in timely puberty onset in the ewe. Western Virginia Univ Thesis.

Objective: To investigate the role of arcuate nucleus KNDy (kisspeptin/neurokinin B/dynorphin) neurons in regulating the timing of puberty onset and estradiol (E2) sensitivity in female sheep.

Summary: Ablation of approximately 75% of KNDy neurons using NKB-SAP in the arcuate nucleus significantly delayed puberty onset and blunted the luteinizing hormone (LH) surge, demonstrating that KNDy neurons are critical for timely puberty in ewes. However, animals retained the ability to respond to NK3R agonist senktide, suggesting upstream populations may mediate estradiol negative feedback.

Usage: NKB-SAP (IT-63) was bilaterally injected into the arcuate nucleus (1 µg/side in 1 µL) to ablate NK3R-expressing KNDy neurons and evaluate their role in pubertal timing and LH regulation.

Related Products: NKB-SAP (Cat. #IT-63)

Morroni F, Caccamo A (2024) Advances and Challenges in Gene Therapy for Alzheimer’s Disease. J Alzheimers Dis 101(s1):S417-S431. doi: 10.3233/JAD-230783 PMID: 39422937

Objective: Provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of Alzheimer’s Disease (AD), highlighting their potential as novel therapeutic strategies.

Summary: Gene therapy offers the potential for long-term benefits by providing sustained therapeutic effects. By modifying or replacing faulty genes, it may slow down or halt the progression of AD. Vector-based genetic therapies have demonstrated promising results in mouse models, but face hurdles such as managing risks associated with vectors and delivery methods.

Usage: Rats with cholinergic deficit were induced by intraseptal injection of 192-IgG-SAP (IT-01).

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

See Also:

• Dobryakova YV et al. Intrahippocampal adeno-associated virus-mediated overexpression of nerve growth factor reverses 192IgG-saporin-induced impairments of hippocampal plasticity and behavior. Front Neurosci 15:745050, 2021.

Thomson AC (2024) Puberty-associated changes in Kiss1r, MC3R, and MC4R in the ewe. West Virginia Univ Thesis.

Objective: To examine kisspeptin receptor (Kiss1r) mRNA expression in gonadotropin releasing hormone (GnRH) neurons and melanocortin 3 and 4 receptor (MC3R/MC4R) expression in kisspeptin neurons across pubertal development.

Summary: Kiss1r expression in GnRH neurons increased with development. In the arcuate nucleus (ARC), the proportion of kisspeptin neurons expressing MC3R, but not MC4R, also rose, though MC3R signal intensity remained unchanged. ARC Kiss1r expression did not vary. Findings support increased GnRH neuron sensitivity to kisspeptin and aMSH as part of the pubertal neurocircuitry.

Usage: Author references prior studies. Deletion of about 75% of KNDy neurons through targeted NKB-SAP (IT-63) injections significantly delayed puberty onset. Reduction of Kiss1r expression in the ARC via targeted injection of a Kisspeptin-SAP (IT-102) conjugate disrupted pulsatile LH release and blocked the LH surge.

Related Products: NKB-SAP (Cat. #IT-63), Kisspeptin-SAP (Cat. #IT-102)

See Also:

• Aerts EG et al. The effect of NK3-Saporin injection within the arcuate nucleus on puberty, the LH surge, and the response to Senktide in female sheep. Biol Reprod 110(2):275-287, 2024.

Kudsi SQ, Viero FT, Pereira LG, Trevisan G (2024) Involvement of the transient receptor channels in preclinical models of musculoskeletal pain. Curr Neuropharmacol 22(1):72-87. doi: 10.2174/1570159X21666230908094159 PMID: 37694792

Objective: To provide an updated view of the most studied preclinical models of muscle hyperalgesia and the role of transient receptor potential (TRP) in these models.

Summary: The participation of TRPV1, TRPA1, and TRPV4 in different models of musculoskeletal pain was evaluated using pharmacological and genetic tools. All the studies detected the antinociceptive effect of respective antagonists or reduced nociception in knockout mice. Hence, TRPV1, TRPV4, and TRPA1 blockers could potentially be utilized in the future for inducing analgesia in muscle hypersensitivity pathologies.

Usage: NK1-expressing neurons were ablated by SP-SAP (neurotoxin saporin conjugated to substance P) to Vc, and the ablation of NK1-expressing second-order neurons reduced the MGS and bite force nociceptive behaviors.

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

See Also:

• Wang S, Lim J, Joseph J, Wang S, Wei F, Ro JY, Chung MK. Spontaneous and Bite-Evoked Muscle Pain Are Mediated by a Common Nociceptive Pathway With Differential Contribution by TRPV1. J Pain. 2017 Nov;18(11):1333-1345. doi: 10.1016/j.jpain.2017.06.005. Epub 2017 Jun 29. PMID: 28669862

Edwards CM, Guerrero IE, Thompson D, Dolezel T, Rinaman L (2024) An ascending vagal sensory-central noradrenergic pathway modulates retrieval of passive avoidance memory. bioRxiv 2024.04.09.588717. doi: 10.1101/2024.04.09.588717 PMID: 38645069

Objective: To investigate the role of a gut vagal afferent-to-central noradrenergic pathway in modulating the retrieval of conditioned passive avoidance memory in rats.

Summary: This study explores how visceral sensory feedback via vagal afferents and central noradrenergic neurons influences passive avoidance memory retrieval. By lesioning specific neural pathways in adult male rats, the researchers demonstrate that disruption of these circuits significantly increased conditioned passive avoidance behavior, suggesting a critical role for these pathways in integrating interoceptive signals with contextual cues to modulate learned avoidance behaviors.

Usage: 250 ng of CCK-SAP (IT-31) was bilaterally injected into the nodose ganglion to selectively lesion gastrointestinal vagal afferents. 80 ng of Anti-DBH-SAP (IT-03) was injected bilaterally into the ventrolateral bed nucleus of the stria terminalis (vlBNST) to selectively lesion noradrenergic inputs to the anterior vlBNST.

Related Products: CCK-SAP (Cat. #IT-31), Anti-DBH-SAP (Cat. #IT-03)

Kumbhare D, Rajagopal M, Toms J, Freelin A, Weistroffer G, McComb N, Karnam S, Azghadi A, Murnane KS, Baron MS, Holloway KL (2024) Deep brain stimulation of nucleus basalis of meynert improves learning in rat model of dementia. bioRxiv 2024.04.05.588271. doi: 10.1101/2024.04.05.588271 PMID: 38645266

Objective: To assess the effects of varying stimulation patterns and duration on learning in a dementia rat model.

Summary: Deep brain stimulation (DBS) of nucleus basalis of Meynert (NBM) has been considered a potential treatment for dementia, but more study is needed to determine the ideal parameters for NBM stimulation. 192-IgG-SAP (Cat. IT-01) was used to lesion cholinergic neurons of rats creating a rat model of dementia upon which NBM deep brain stimulation could be tested. The desired destruction of neurons was 70-80% cholinergic population lesioned, which through a panel of concentrations was determined to be a 0.50 μg dose. The rat models of dementia were then tested for ideal type and duration of deep brain stimulation to improve operant learning test performance.

Usage: 192-IgG-SAP was bilaterally injected in the NBM in the following amounts: 0.00 (control), 0.15, 0.30, 0.50, and 0.75 μg in 0.5 μl PBS.

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

Wei J, Liu H, Zhou F, Zhang H, Zhang L (2024) The recent research progress in neurobiological characteristics and pain regulation of the cerebrospinal fluid-contacting nucleus. Anesthesiology and Perioperative Science 2(17) doi: 10.1007/s44254-024-00051-9

Objective: To provide novel insights into the investigation of pain regulation within bidirectional regulatory pathway between the brain and cerebrospinal fluid, with a specific focus one elucidating the role of the CSF-contacting nucleus as a bridge structure.

Summary: Studies revealed that the targeted destruction of the CSF-contacting nucleus and reduction in the basic pain threshold were achieved by introducing CB-saporin (SAP) into the lateral ventricle, thereby facilitating the pain behavior response in the pain model.

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

See Also:

• Liu H et al. Role of the cerebrospinal fluid-contacting nucleus in the descending inhibition of spinal pain transmission. Exp Neurol 261:475-485, 2014.
• Cao J et al. [Targeted damage of the cerebrospinal fluid-contacting nucleus contributes to the pain behavior and the expression of 5-HT and c-Fos in spinal dorsal horn of rats]. Zhongguo Ying Yong Sheng Li Xue Za Zhi 30:218-222, 2014.

Jiao L, Kang H, Geng Y, Liu X, Wang M, Shu K (2024) The role of the nucleus basalis of meynert in neuromodulation therapy: A systematic review from the perspective of neural network oscillations. Front Aging Neurosci 16:1376764. doi: 10.3389/fnagi.2024.1376764 PMID: 38650866

Objective: To review previous animal studies of NBM lesions, NBM-DBS models, and clinical case studies to summarize the important functions of the NBM in neuromodulation.

Summary: Authors reviewed studies showing effects of the NBM on the neural network in arousal, sleep and epilepsy, effects of the NBM on the neural network –evidence from NBM injury animal models, and neuromodulation effects of NBM-DBS in animal models.

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

See Also:

• Berdiev RK et al. The role of the nucleus basalis of Meynert and reticular thalamic nucleus in pathogenesis of genetically determined absence epilepsy in rats: A lesion study. Brain Res 1185:266-274, 2007.
• Ljubojevic V et al. Cholinergic modulation of frontoparietal cortical network dynamics supporting supramodal attention. J Neurosci 38:3988-4005, 2018.
• Berntson GG et al. Specific contributions of the basal forebrain corticopetal cholinergic system to electroencephalographic activity and sleep/waking behaviour. Eur J Neurosci 16(12):2453-2461, 2002.
• Dezawa S et al. Lesions of the nucleus basalis magnocellularis (Meynert) induce enhanced somatosensory responses and tactile hypersensitivity in rats. Exp Neurol 335:113493, 2021.

MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P (2024) Informed by cancer stem cells of solid tumors: Advances in treatments targeting tumor-promoting factors and pathways. Int J Mol Sci 25(7):4102. doi: 10.3390/ijms25074102 PMID: 38612911

Objective: To provide a comprehensive overview of the therapeutic targets associated with cancer stem cells (CSCs) of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog.

Summary: Notably, many of the molecular targets and pathways associated with CSCs are also expressed in normal physiological processes and other stem cell populations. This presents a significant hurdle, as on-target effects of therapeutic interventions could inadvertently impact normal tissue function, leading to potential toxicity and adverse effects.

Usage: Bostad et al. used photochemical internalization to deliver Anti-CD133-SAP (IT-82) to WiDr colon cancer tumor-bearing mice, resulting in a significant decrease in tumor growth compared to control.

Related Products: Anti-CD133-SAP (Cat. #IT-82)

See Also:

• Bostad M et al. Light-controlled endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin by photochemical internalization – A minimally invasive cancer stem cell-targeting strategy. J Control Release 206:37-48, 2015.