Gadolinium-based contrast agents aggravate mechanical and thermal hyperalgesia in a nitroglycerine-induced migraine model in male mice.

In the diagnosis of migraine, which is a neurovascular disease, gadolinium-based contrast agents (GBCAs) are used to rule out more serious conditions. On the other hand, it remains unclear as a scientific gap whether GBCAs may trigger migraine-related pain. The aim of this study was to investigate the effect of GBCAs on mechanical and thermal pain behaviour in a nitroglycerin (NTG)-induced migraine model in mice. NTG (10 mg/kg) was administered intraperitoneally to adult (6-8weeks old) BALB/c mice 2 h before behavioral tests 5 times every other day on days 1st, 3rd, 5th and 9th to induce migraine model (N = 50). As GBCAs, gadobenate dimeglumine (linear-ionic), Gadodiamide (linear-nonionic), and gadobutrol (macrocyclic-nonionic) were delivered intravenously through the tail vein of mice for 5 days on test days. Mechanical pain threshold (plantar and facial withdrawal threshold) was evaluated by plantar von Frey and periorbital von Frey tests on days 1st, 5th, and 9th, and thermal pain threshold (latency) was evaluated by hot plate and cold plate tests on days 3rd and 7th. There was a statistically significant increase in mechanical and thermal hyperalgesia in NTG administered groups compared to the control group. Gadodiamide, gadobutrol and gadobenate dimeglumine administration significantly decreased latency, paw and facial withdrawal threshold (0.18 ± 0.05, 0.17 ± 0.07, 0.16 ± 0.09; 9th day values respectively) compared to NTG group (0.27 ± 0.05). The results of this in vivo study show that GBCAs produce effects that may trigger migraine attacks in migraine. It is recommended that these effects be further investigated and supported by further clinical studies.

Humanin's impact on pain markers and neuronal viability in diabetic neuropathy model.

OBJECTIVE: This study investigates the impact of chronic humanin (HN) treatment on pain-related markers (NMDA, substance P, TRPV1, and IL-1ß) in diabetic mice's dorsal root ganglia (DRG). Additionally, we assess the effects of HN on cellular viability in DRG neurons. METHODS: In vivo experiments involved 15 days of HN administration (4 mg/kg) to diabetic mice (n = 10). Protein levels of NMDA, IL-1ß, TRPV1, and substance P were measured in diabetic DRG. In vitro experiments explored HN's impact on apoptosis and cellular viability, focusing on the JAK2/STAT3 pathway. RESULTS: Humanin significantly reduced the elevated expression of NMDA, IL-1ß, TRPV1, and substance P induced by diabetes (p < .05). Furthermore, HN treatment increased cellular viability in DRG neurons through JAK2/STAT3 pathway activation (p < .05). CONCLUSION: These findings highlight the significance of understanding mitochondrial function and pain markers, as well as apoptosis in diabetes. The study provides insights for managing the condition and its complications.

Modulation of Neuronal Damage in DRG by Asprosin in a High-Glucose Environment and Its Impact on miRNA181-a Expression in Diabetic DRG.

Asprosin, a hormone secreted from adipose tissue, has been implicated in the modulation of cell viability. Current studies suggest that neurological impairments are increased in individuals with obesity-linked diabetes, likely due to the presence of excess adipose tissue, but the precise molecular mechanism behind this association remains poorly understood. In this study, our hypothesis that asprosin has the potential to mitigate neuronal damage in a high glucose (HG) environment while also regulating the expression of microRNA (miRNA)-181a, which is involved in critical biological processes such as cellular survival, apoptosis, and autophagy. To investigate this, dorsal root ganglion (DRG) neurons were exposed to asprosin in a HG (45 mmol/L) environment for 24 hours, with a focus on the role of the protein kinase A (PKA) pathway. Expression of miRNA-181a was measured by using real-time polymerase chain reaction (RT-PCR) in diabetic DRG. Our findings revealed a decline in cell viability and an upregulation of apoptosis under HG conditions. However, pretreatment with asprosin in sensory neurons effectively improved cell viability and reduced apoptosis by activating the PKA pathway. Furthermore, we observed that asprosin modulated the expression of miRNA-181a in diabetic DRG. Our study demonstrates that asprosin has the potential to protect DRG neurons from HG-induced damage while influencing miRNA-181a expression in diabetic DRG. These findings provide valuable insights for the development of clinical interventions targeting neurotoxicity in diabetes, with asprosin emerging as a promising therapeutic target for managing neurological complications in affected individuals.

Asprosin, a novel glucogenic adipokine: a potential therapeutic implication in diabetes mellitus.

OBJECTIVES: We aimed to investigate the effects of asprosin on diabetes with a focus on serum glucose, irisin, ghrelin, leptin levels and hepatic levels of triglycerides (TG), cholesterol, low-density lipoprotein (LDL). METHODS: Asprosin (10 µg/kg) was administered intraperitoneally four times at 3-day intervals and then blood and hepatic parameters above mentioned were investigated in control and diabetic mice. RESULTS: The administration of asprosin increased blood glucose level in healthy animals (p = .05) whereas it did not change blood glucose level in diabetic animals. In addition, while asprosin decreased irisin level and increased ghrelin level, it did not change leptin level in diabetic mice. Therewithal, asprosin decreased the increasing levels in hepatic TG, cholesterol, and LDL in diabetic mice. CONCLUSIONS: Our novel findings implicate that asprosin may be a target molecule in preventing the development and complications of diabetes.

Crosstalk between kisspeptin and gonadotropin-inhibitory hormone in the silence of puberty: preclinical evidence from a calcium signaling study.

Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are among suggested neuroendocrine modulators of reproductive function. Intracellular calcium signaling is a critical component in the regulation of a variety of physiological and pathological processes including neurotransmitter release, and, therefore, can be used as signaling indicator for investigating the involvement of kisspeptin, GnIH, and gonadotropin-releasing hormone (GnRH) release. Hence, this study investigated the effects of kisspeptin and GnIH on calcium signaling using immortalized hypothalamic cells (rHypoE-8) as a model. Kisspeptin neurons were loaded with the ratiometric calcium dye (Fura-2 AM, 1 µmol) and intracellular free calcium ([Ca2+]i) responses were quantified using digital fluorescence imaging system. Kisspeptin-10 (100, 300, and 1000 nM) caused a significant increase in [Ca2+]i in rHypoE-8 cells (n = 58, n = 64, and n = 49, respectively, p < 0.001). The kisspeptin receptor antagonist, P234, inhibited the calcium responses to kisspeptin (p < 0.001, n = 32). GnIH (100 and 1000 nM), alone, did not cause any significant change in the mean basal [Ca2+]i levels in kisspeptin cells, but GnIH attenuated the kisspeptin-evoked [Ca2+]i transients (n = 47, p < 0.001). This novel findings of [Ca2+]i signaling in in vitro setting implicate that kisspeptin and GnIH may exert their effects on hypothalamus-pituitary-gonadal (HPG) axis by modulating kisspeptin neurons. These results also implicate that kisspeptin neurons may have an autocrine regulation.

Asprosin, a novel therapeutic candidate for painful neuropathy: an experimental study in mice.

Recent studies indicate presence of a strong link between adipokines and neuropathic pain. However, the effects of asprosin, a novel adipokine, on neuropathic pain have not been studied in animal models.Mouse models were employed to investigate the antinociceptive effectiveness of asprosin in the treatment of three types of neuropathic pain, with metabolic (streptozocin/STZ), toxic (oxaliplatin/OXA), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, respectively. Changes in nociceptive behaviors were assessed relative to controls using thermal (the hot plate and cold plate tests, at 50 °C and 4 °C respectively) and mechanical pain (von Frey test) tests after intraperitoneal (i.p.) administration of asprosin (10 µg/kg) and gabapentin (50 mg/kg) in several times intervals. Besides, possible effect of asprosin on the motor coordination of mice was assessed with a rotarod test. Serum level of asprosin was quantified by ELISA.In neuropathic pain models (STZ, OXA, and CCI), asprosin administration significantly reduced both mechanical and thermal hypersensitivity, indicating that it exhibits a clear-cut antihypersensitivity effect in the analyzed neuropathic pain models. The most effective time of asprosin on pain threshold was observed 60 min after its injection. Also, asprosin displayed no notable effect on the motor activity. Asprosin levels were significantly lower in neuropathic pain compared to healthy group (p < 0.05).The results yielded by the present study suggest that asprosin exhibits an analgesic effect in the neuropathic pain models and may have clinical utility in alleviating chronic pain associated with disease and injury originating from peripheral structures.

Agomelatine modulates calcium signaling through protein kinase C and phospholipase C-mediated mechanisms in rat sensory neurons.

Agomelatine, a novel antidepressant exerting its effects through melatonergic and serotonergic systems, implicated to be effective against pain including neuropathic pain but without any knowledge of mechanism of action. To explore the possible role of agomelatine on nociceptive transmission at the peripheral level, the effects of agomelatine on intracellular calcium ([Ca2+ ]i ) signaling in peripheral neurons were investigated in cultured rat dorsal root ganglion (DRG) neurons. Using the fura-2-based calcium imaging technique, the effects of agomelatine on [Ca2+ ]i and roles of the second messenger-mediated pathways were assessed. Agomelatine caused [Ca2+ ]i signaling in a dose-dependent manner when tested at 10 and 100 µM concentration. Luzindole, a selective melatonin receptor antagonist, almost completely blocked the agomelatine-induced calcium signals. The agomelatine-induced calcium transients were also nearly abolished following pretreatment with the 100 ng/ml pertussis toxin, a Gi/o protein inhibitor. The stimulatory effects of agomelatine on [Ca2+ ]i transients were significantly reduced by applications of phospholipase C (PLC) and protein kinase C (PKC) blockers, 10 µM U73122, and 10 µM chelerythrine chloride, respectively. The obtained results of agomelatine-induced [Ca2+ ]i signals indicates that peripheral mechanisms are involved in analgesic effects of agomelatine. These mechanisms seems to involve G-protein-coupled receptor activation and PLC and PKC mediated mechanisms.