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Lomeli, N.

Publications and source records attributed to Lomeli, N..

4 recordsLinked to original sources
bioRxiv2024

Reduced Capsaicin-Induced Mechanical Allodynia and Neuronal Responses in the DRG in the Presence of Shp1 Overexpression

Transient Receptor Potential Vanilloid 1 (TRPV1) is a nonselective cation channel expressed by pain-sensing neurons and has been an attractive target for the development of drugs to treat pain. Recently, Src homology region 2 domain-containing phosphatase-1 (SHP-1) was shown to dephosphorylate TRPV1 in dorsal root ganglia (DRG) neurons, which was linked with alleviating different pain phenotypes. These previous studies were performed in male rodents only and did not directly investigate the role of SHP-1 in TRPV-1 mediated sensitization. Therefore, our goal was to determine the impact of Shp1 overexpression on TRPV1-mediated neuronal responses and capsaicin-induced pain behavior in mice of both sexes. Twelve-week-old male and female mice overexpressing Shp1 (Shp1-Tg) and their wild type (WT) littermates were used. Shp1 overexpression was confirmed in the DRG of Shp1-Tg mice by RNA in situ hybridization and RT-qPCR. Trpv1 and Shp1 were found to be co-expressed in DRG sensory neurons in both genotypes. Functionally, this overexpression resulted in lower magnitude intracellular calcium responses to 200 nM capsaicin stimulation in DRG cultures from Shp1-Tg mice compared to WTs. In vivo, we tested the effects of Shp1 overexpression on capsaicin-induced pain through a model of capsaicin footpad injection. While capsaicin injection evoked nocifensive behavior (paw licking) and paw swelling in both genotypes and sexes, only WT mice developed mechanical allodynia after capsaicin injection. We observed similar level of TRPV1 protein expression in the DRG of both genotypes, however, a higher amount of tyrosine phosphorylated TRPV1 was detected in WT DRG. These experiments suggest that, while SHP-1 does not mediate the acute swelling and nocifensive behavior induced by capsaicin, it does mediate a protective effect against capsaicin-induced mechanical allodynia in both sexes. The protective effect of SHP-1 might be mediated by TRPV1 dephosphorylation in capsaicin-sensitive sensory neurons of the DRG.

neuroscience↗
bioRxiv2023

Cisplatin Induces BDNF Downregulation in Middle-Aged Female Rat Model while BDNF Enhancement Attenuates Cisplatin Neurotoxicity

Cancer-related cognitive impairments (CRCI) are debilitating consequences of cancer treatment with platinum agents (e.g., cisplatin) that greatly alter cancer survivors health-related quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning, and memory, and the reduction of BDNF is associated with the development of cognitive impairment in various neurological disorders, including CRCI. Our previous CRCI rodent studies have shown that cisplatin reduces hippocampal neurogenesis and BDNF expression and increases hippocampal apoptosis, which is associated with cognitive impairments. Few studies have reported on the effects of chemotherapy and medical stress on serum BDNF levels and cognition in middle-aged female rat models. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive performance in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected ten weeks after cisplatin completion. We also screened three BDNF-augmenting compounds, riluzole, ampakine CX546, and CX1739, for their neuroprotective effects on hippocampal neurons, in vitro. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD95. Ampakines (CX546 and CX1739) but not riluzole altered the antitumor efficacy of cisplatin in two human ovarian cancer cell lines, OVCAR8 and SKOV3.ip1, in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels with cognitive function. We conducted an in vitro screening of BDNF-enhancing agents to evaluate their potential neuroprotective effects against cisplatin-induced neurotoxicity and their effect on ovarian cancer cell viability.

neuroscience↗