Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea

Bhatta, Puspanjali; Dhukhwa, Asmita; Sheehan, Kelly; Aameri, Raheem F. H. Al; Borse, Vikrant; Ghosh, Sumana; Sheth, Sandeep; Mamillapalli, Chaitanya; Rybak, Leonard P.; Ramkumar, Vickram; Mukherjea, Debashree

doi:10.1038/s41598-019-40425-9

Cited by 35 publications

(37 citation statements)

References 53 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, TRPV1 receptors and cannabinoid receptors share some signaling pathways in various cell types [ 30 , 31 , 32 , 33 , 34 , 35 ]. Several groups have demonstrated the activation of TRPV1 receptors by endocannabinoids, so there is a possibility that Capsaicin may activate cannabinoid receptors as well [ 32 , 36 ]. In this way, the effect of Capsaicin was explored after inhibiting CB 1 or CB 2 receptors with specific antagonists.…”

Section: Discussionmentioning

confidence: 99%

Capsaicin Causes Vasorelaxation of Rat Aorta through Blocking of L-type Ca2+ Channels and Activation of CB1 Receptors

et al. 2020

View full text Add to dashboard Cite

The aim of this work was to determine whether Capsaicin may exert a vascular regulation through the activation of CB1 and/or CB2 receptors causing vasorelaxation in the rat aorta. Our results show the location of TRPV1 mainly in the endothelial and smooth muscle cells membrane. Nevertheless, Capsaicin caused vasorelaxation of this artery through a mechanism independent of TRPV1, since the specific antagonists Capsazepine and SB-366791 did not block the effect of Capsaicin. Because the significant expression of CB1 and CB2 receptors has been previously reported in the rat aorta, we used antagonists for these two receptors prior to the addition of Capsaicin. In these experiments, we found that the inhibition of CB1 using AM281, decreases the vasorelaxant effect caused by Capsaicin. On the other hand, the vasorelaxant effect is not altered in the presence of the CB2 receptor antagonist AM630. Furthermore, a partial decrease of the effect of Capsaicin was also seen when L-type calcium channels are blocked. A complete block of Capsaicin-induced vasorelaxation was achieved using a combination of Verapamil and AM281. In accordance to our results, Capsaicin-induced vasorelaxation of the rat aorta is neither dependent of TRPV1 or CB2 receptors, but rather it is strongly suggested that a tandem mechanism between inactivation of L-type calcium channels and the direct activation of CB1 receptors is involved. These findings are supported by CB1 docking simulation which predicted a binding site on CB1 receptors for Capsaicin.

show abstract

Section: Discussionmentioning

confidence: 99%

Capsaicin Causes Vasorelaxation of Rat Aorta through Blocking of L-type Ca2+ Channels and Activation of CB1 Receptors

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Cisplatin-associated ototoxicity is a major complication of cisplatin-based chemotherapy (2,3,5). cisplatin-induced (10,(12)(13)(14). The present study demonstrated that cisplatin-induced ototoxicity in Hei-oc1 auditory cells was associated with the inhibition of cell viability and dysregulation of genes related to apoptosis, cell cycle arrest and several pathways, including the p53, HiF-1, Wnt and Pi3K-akt signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Several drugs with antagonistic effects against cisplatininduced cytotoxicity, dna damage, and apoptosis in cochlear hair cells might represent potential treatment strategies for cisplatin-induced ototoxicity (10,(12)(13)(14). For instance, tetramethylpyrazine (Tet) and tanshinone iia (Tan iia) can protect against hearing impairment and ototoxicity induced by aminoglycoside antibiotics, cisplatin, and radiation (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Identifying the mechanisms underlying the protective effect of tetramethylpyrazine against cisplatin‑induced in vitro ototoxicity in HEI‑OC1 auditory cells using gene expression profiling

et al. 2020

View full text Add to dashboard Cite

Sensorineural hearing loss is prevalent in patients receiving cisplatin therapy. Tetramethylpyrazine (Tet) and tanshinone iia (Tan iia) have protective roles against hearing impairment or ototoxicity. The present study aimed to investigate the molecular mechanisms underlying cisplatin-induced ototoxicity and the protective effect of Tet and Tan iia against it. House ear institute-organ of corti 1 auditory cells were treated with titrating doses of Tan iia, Tet, and cisplatin. in a cell viability assay, cisplatin, Tan iia and Tet had ic 50 values of 42.89 µM, 151.80 and 1.04x10 3 mg/l, respectively. Tan iia augmented cisplatin-induced cytotoxicity. However, Tet concentrations <75 mg/l attenuated cisplatin-induced cytotoxicity and apoptosis. Moreover, rna sequencing analysis was carried out on auditory cells treated for 30 h with 30 µM cisplatin alone for 48 h or combined with 37.5 mg/l Tet for 30 h. differentially expressed genes (deGs) induced in these conditions were identified and examined using Gene Ontology and Kyoto encyclopedia of Genes and Genomes pathway analysis. cisplatin increased the expression of genes related to the p53 and Foxo pathways, such as Fas, p21/cdKn1a, and Bcl-2 binding component 3, but decreased the expression of insulin-like growth factor 1 (iGF1), as well as genes in the histone (Hist)1 and Hist2 clusters. Treatment with Tet downregulated FoXo3 and Bcl-2 binding component 3, and increased the expression of iGF1. Moreover, Tet upregulated genes associated with Wnt signaling, but not p53-related genes. Thus, the otoprotective properties of Tet might be mediated by activation of Wnt and iGF1 signaling, and inhibition of Foxo signaling.

show abstract

“…In addition to these targets, however, several other EC mechanisms (mainly related to inflammation) are present in the auditory system and in other CNS regions important for tinnitus ( Figure 2 ). A protective EC mechanism is present in the cochlea ( 224 , 225 ). Moreover, animal studies show inflammatory responses in the auditory cortex after tinnitus induction ( 154 , 226 ), and inflammatory responses in the cochlea ( 154 , 227 , 228 ) and cochlear nuclei ( 229 – 232 ) after tinnitus-inducing treatments.…”

Section: Introductionmentioning

confidence: 99%

Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective

et al. 2020

View full text Add to dashboard Cite

Cannabis has been used for centuries for recreational and therapeutic purposes. Whereas, the recreative uses are based on the psychotropic effect of some of its compounds, its therapeutic effects range over a wide spectrum of actions, most of which target the brain or the immune system. Several studies have found cannabinoid receptors in the auditory system, both at peripheral and central levels, thus raising the interest in cannabinoid signaling in hearing, and especially in tinnitus, which is affected also by anxiety, memory, and attention circuits where cannabinoid effects are well described. Available studies on animal models of tinnitus suggest that cannabinoids are not likely to be helpful in tinnitus treatment and could even be harmful. However, the pharmacology of cannabinoids is very complex, and most studies focused on neural CB1R-based responses. Cannabinoid effects on the immune system (where CB2Rs predominate) are increasingly recognized as essential in understanding nervous system pathological responses, and data on immune cannabinoid targets have emerged in the auditory system as well. In addition, nonclassical cannabinoid targets (such as TRP channels) appear to play an important role in the auditory system as well. This review will focus on neuroimmunological mechanisms for cannabinoid effects and their possible use as protective and therapeutic agents in the ear and auditory system, especially in tinnitus.

show abstract

Capsaicin Protects Against Cisplatin Ototoxicity by Changing the STAT3/STAT1 Ratio and Activating Cannabinoid (CB2) Receptors in the Cochlea

Cited by 35 publications

References 53 publications

Capsaicin Causes Vasorelaxation of Rat Aorta through Blocking of L-type Ca2+ Channels and Activation of CB1 Receptors

Capsaicin Causes Vasorelaxation of Rat Aorta through Blocking of L-type Ca2+ Channels and Activation of CB1 Receptors

Identifying the mechanisms underlying the protective effect of tetramethylpyrazine against cisplatin‑induced in vitro ototoxicity in HEI‑OC1 auditory cells using gene expression profiling

Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective

Contact Info

Product

Resources

About