RESUMEN
The present study aimed to investigate the role of agmatine in the neurobiology underlying memory impairment during ethanol withdrawal in rats. Sprague-Dawley rats were subjected to a 21-day chronic ethanol exposure regimen (2.4 % w/v ethanol for 3 days, 4.8 % w/v for the next 4 days, and 7.2 % w/v for the following 14 days), followed by a withdrawal period. Memory impairment was assessed using the passive avoidance test (PAT) at 24, 48, and 72 h post-withdrawal. The ethanol-withdrawn rats displayed a significant decrease in step-through latency in the PAT, indicative of memory impairment at 72 h post-withdrawal. However, administration of agmatine (40 µg/rat) and its modulators (L-arginine, arcaine, and amino-guanidine) significantly increases the latency time in the ethanol-withdrawn rats, demonstrating the attenuation of memory impairment. Further, pretreatment with imidazoline receptor agonists enhances agmatine's effects, while antagonists block them, implicating imidazoline receptors in agmatine's actions. Neurochemical analysis in ethanol-withdrawn rats reveals dysregulated glutamate and GABA levels, which was attenuated by agmatine and its modulators. By examining the effects of agmatine administration and modulators of endogenous agmatine, the study aimed to shed light on the potential therapeutic implications of agmatinergic signaling in alcohol addiction and related cognitive deficits. Thus, the present findings suggest that agmatine administration and modulation of endogenous agmatine levels hold potential as therapeutic strategies for managing alcohol addiction and associated cognitive deficits. Understanding the neurobiology underlying these effects paves the way for the development of novel interventions targeting agmatinergic signaling in addiction treatment.
Asunto(s)
Agmatina , Disfunción Cognitiva , Etanol , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias , Animales , Agmatina/farmacología , Agmatina/uso terapéutico , Síndrome de Abstinencia a Sustancias/metabolismo , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/psicología , Masculino , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Ratas , Biguanidas/farmacología , Ácido Glutámico/metabolismo , Arginina/farmacología , Ácido gamma-Aminobutírico/metabolismo , Receptores de Imidazolina/metabolismo , Receptores de Imidazolina/agonistas , Reacción de Prevención/efectos de los fármacosRESUMEN
BACKGROUND: In the last few decades, cancer immunotherapy has been extensively researched, and novel checkpoint signaling mechanisms involving Programmed Death (PD)-1 and PDLigand 1 (PD-L1) receptors have been targeted. The PD-1/PD-L1 binding and interaction play a critical role in the development of malignancies. OBJECTIVE: The present review focuses on recent patents on the pharmacological and biological cancerregulating properties of PD-1/PD-L1 inhibitors involved in immunotherapeutic cancer drug development. METHODS: Thorough patent literature search published during the last seven years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents, to identify PD-1/PD-L1-targeting small molecule immunomodulators. RESULTS: Several small molecule PD-1/PD-L1 inhibitors were patented for regulation of tumor progression by academic and industry-associated investigators. Most of the claimed patents have been validated and confined to in vitro and in vivo mouse models limiting their entry into clinical settings. Majority of the patents are claimed by the researchers at Aurigene Ltd. (India) on novel peptidomimetic compounds. It is worth to be noted that macrocyclic compounds such as the peptides QP20, HD20, WQ20, SQ20, and CQ-22 from Bristol-Myers Squibb (BMS) Company, biaryl, and heterocyclic derivatives including 1,3-dihydroxy-phenyl compounds were efficient in regulating the PD-1/PD-L1 protein-protein binding and interaction compared to those of the approved monoclonal antibodies. CONCLUSION: PD-1/PD-L1 inhibitors show significant anti-cancer responses as stand-alone agents and in combination with other cancer therapies. More efficient experimental studies and clinical trials are necessary to evaluate the host-tumor cells' interactions. Understanding the cancer microenvironment, and identifying specific biomarkers and X-ray crystalline structures of PD-1/PD-L1 complexes, including molecular and genomic signature studies are essential to determine the feasibility of PD-1/PD-L1 inhibitors for development into drug-like cancer immunotherapeutics.
Asunto(s)
Antineoplásicos , Antígeno B7-H1/inmunología , Inmunoterapia , Neoplasias/terapia , Patentes como Asunto , Receptor de Muerte Celular Programada 1/inmunología , Animales , Anticuerpos Monoclonales/economía , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/clasificación , Antineoplásicos/economía , Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/economía , Antineoplásicos Inmunológicos/uso terapéutico , Humanos , Inmunoterapia/economía , Inmunoterapia/métodos , Inmunoterapia/normas , Ligandos , Ratones , Neoplasias/inmunología , Patentes como Asunto/estadística & datos numéricos , Bibliotecas de Moléculas Pequeñas/análisisRESUMEN
BACKGROUND: Inflammasomes are recognized as key regulators in innate immunity from the pathogenic to endogenous danger signals. Although controlled activation of inflammasome is highly beneficial, dysregulation of inflammasome activation plays central role in various autoimmune, inflammatory disorders and aid in promoting various forms of cancers in humans such as breast cancer, fibrosarcoma, gastric carcinoma, and lung metastasis. NLRP3 inflammasome activation has been emerged as a topic of interest and is under profound investigation for its involvement in multiple forms of cancers. OBJECTIVE: This review emphasizes an overview of the recent patents on NLRP3 inflammasome activation inhibitors with their relevant biological/pharmacological properties for the prevention and treatment of inflammation-associated cancer disorders. METHODS: Data were obtained from online patent searchers such as World Intellectual Property Organization (WIPO®), Free Patent Online (FPO), Espacenet® and Google Patents. RESULTS: Several NLRP3 inflammasome activation inhibitors were recently patented from naturally derived and synthetic agents mainly by academic researchers. Most of the claimed patents have been validated and confined to cell lines and animal models limiting their entry into clinical settings. CONCLUSION: The vigorous effort to discover and develop agents to specifically inhibit NLRP3 inflammasome activation, may pave the way to therapeutic intervention targeting inflammasome-regulated pathways that are involved in the pathogenesis of various forms of cancer.