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Age-related obesity is a growing healthcare burden. Effectiveness of body weight reducing mediators changes with aging and these alterations may contribute to aging obesity. Our previous results suggested a potential contributions of urocortin 2 (UCN2) to aging obesity and age-related cachexia. Lifestyle interventions, such as caloric restriction or physical activity can improve body weight and body composition. Previous observations suggest that lifestyle interventions may also influence age-associated regulatory changes in energy balance. We aimed to study the effects of a 12-week treadmill training or caloric restriction on the central hypermetabolic responsiveness to UCN2 in middle-aged 6- and 12-month old male Wistar rats. Interventions started at age 3- or 9-months. Following the interventions, acute hypermetabolic/hyperthermic responses were tested upon intracerebroventricular injections of UCN2. Both the training and the caloric restriction lead to weight loss and training led to favorable body composition changes. UCN2-induced hypermetabolism/hyperthermia was diminished by both interventions in both age-groups. The Ucn2 mRNA expression detected by RNAscope in situ hybridization in the hypothalamic paraventricular nucleus was also decreased by both interventions. UCN2-induced hypermetabolism/hyperthermia in the trained and caloric restricted middle-aged groups resembled those of young adult 3-month rats. Lifestyle interventions appear to delay age-related regulatory alterations of energy balance.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca 2+ -binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced ABR wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.

In this study, we investigate the cardiotoxic effects of the well-known cytostatic agent imatinib mesylate (Gleevec), and presented evidence for the cardioprotective effect of BGP-15 which is a novel insulin sensitizer. The cardiotoxic effect of imatinib mesylate was assessed in Langendorff rat heart perfusion system. The cardiac high-energy phosphate levels (creatine phosphate (PCr) and ATP) were monitored in situ by 31 P NMR spectroscopy. The protein oxidation, lipid peroxidation, and the activation of signaling pathways were determined from the freeze-clamped hearts. Prolonged treatment of the heart with imatinib mesylate (20 mg/kg) resulted in cardiotoxicity, which were characterized by the depletion of high-energy phosphates (PCr and ATP), and significantly increased protein oxidation and lipid peroxidation. Imatinib mesylate treatment-induced activation of MAP kinases (including ERK1/2, p38, and JNK) and the phosphorylation of Akt and GSK-3beta. BGP-15 (200 μM) prevented the imatinib mesylate-induced oxidative damages, attenuated the depletion of high-energy phosphates, altered the signaling effect of imatinib mesylate by preventing p38 MAP kinase and JNK activation, and induced the phosphorylation of Akt and GSK-3beta. The suppressive effect of BGP-15 on p38 and JNK activation could be significant because these kinases contribute to the cell death and inflammation in the isolated perfused heart.

Hydrogen sulfide (H2S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H2S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na2S) and slow-releasing (GYY4137) H2S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1−/−) and wild-type (Trpa1+/+) mice. Intracerebroventricular administration of Na2S (0.5–1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na2S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H2S donors was significantly (p < 0.001) attenuated in Trpa1−/− mice compared to their Trpa1+/+ littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H2S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways.

Background The neuropathological background of major depression and anxiety as non-motor symptoms of Parkinson’s disease is much less understood than classical motor symptoms. Although, neurodegeneration of the Edinger–Westphal nucleus in human Parkinson’s disease is a known phenomenon, its possible significance in mood status has never been elucidated. In this work we aimed at investigating whether neuron loss and alpha-synuclein accumulation in the urocortin 1 containing (UCN1) cells of the centrally-projecting Edinger–Westphal (EWcp) nucleus is associated with anxiety and depression-like state in the rat. Methods Systemic chronic rotenone administration as well as targeted leptin–saporin-induced lesions of EWcp/UCN1 neurons were conducted. Rotarod, open field and sucrose preference tests were performed to assess motor performance and mood status. Multiple immunofluorescence combined with RNAscope were used to reveal the functional–morphological changes. Two-sample Student’s t test, Spearman’s rank correlation analysis and Mann–Whitney U tests were used for statistics. Results In the rotenone model, besides motor deficit, an anxious and depression-like phenotype was detected. Well-comparable neuron loss, cytoplasmic alpha-synuclein accumulation as well as astro- and microglial activation were observed both in the substantia nigra pars compacta and EWcp. Occasionally, UCN1-immunoreactive neuronal debris was observed in phagocytotic microglia. UCN1 peptide content of viable EWcp cells correlated with dopaminergic substantia nigra cell count. Importantly, other mood status-related dopaminergic (ventral tegmental area), serotonergic (dorsal and median raphe) and noradrenergic (locus ceruleus and A5 area) brainstem centers did not show remarkable morphological changes. Targeted partial selective EWcp/UCN1 neuron ablation induced similar mood status without motor symptoms. Conclusions Our findings collectively suggest that neurodegeneration of urocortinergic EWcp contributes to the mood-related non-motor symptoms in toxic models of Parkinson’s disease in the rat.

Depression and its increasing prevalence challenge patients, the healthcare system, and the economy. We recently created a mouse model based on the three-hit concept of depression. As genetic predisposition (first hit), we applied pituitary adenylate cyclase-activating polypeptide heterozygous mice on CD1 background. Maternal deprivation modeled the epigenetic factor (second hit), and the chronic variable mild stress was the environmental factor (third hit). Fluoxetine treatment was applied to test the predictive validity of our model. We aimed to examine the dynamics of the epigenetic marker acetyl-lysine 9 H3 histone (H3K9ac) and the neuronal activity marker FOSB in the prefrontal cortex (PFC) and hippocampus. Fluoxetine decreased H3K9ac in PFC in non-deprived animals, but a history of maternal deprivation abolished the effect of stress and SSRI treatment on H3K9ac immunoreactivity. In the hippocampus, stress decreased, while SSRI increased H3K9ac immunosignal, unlike in the deprived mice, where the opposite effect was detected. FOSB in stress was stimulated by fluoxetine in the PFC, while it was inhibited in the hippocampus. The FOSB immunoreactivity was almost completely abolished in the hippocampus of the deprived mice. This study showed that FOSB and H3K9ac were modulated in a territory-specific manner by early life adversities and later life stress interacting with the effect of fluoxetine therapy supporting the reliability of our model.

Although pituitary adenylate cyclase-activating polypeptide (PACAP) was described as a key vasoregulator in human skin, little is known about its expression in mouse skin. As it is important to investigate PACAP signaling in translational mouse dermatitis models, we determined its presence, regulation, and role in neurogenic and non-neurogenic cutaneous inflammatory mechanisms. The mRNA of PACAP and its specific receptor PAC1 was detected with real-time PCR in several skin regions at comparable levels. PACAP-38-immunoreactivity measured with radioimmunoassay was similar in plantar and dorsal paw skin and the ear but significantly smaller in the back skin. PACAP and PAC1 mRNA, as well as PACAP-38 and PAC1 protein expression, significantly increased in the plantar skin after intraplantar administration of capsaicin (50 μl, 100 μg ml−1), an agonist of the transient receptor potential vanilloid 1 (TRPV1) receptor, evoking chiefly neurogenic inflammation without inflammatory cell accumulation. Intraplantar complete Freund’s adjuvant (CFA; 50 μl, 1 mg ml−1) also increased PACAP/PAC1 mRNA but not the PACAP peptide. Capsaicin-induced neurogenic paw edema, but not CFA-evoked non-neurogenic swelling, was significantly smaller in PACAP-deficient mice throughout a 24-hour period. To our knowledge, we provide previously unreported evidence for PACAP and PAC1 expression upregulation during skin inflammation of different mechanisms and for its pro-inflammatory function in neurogenic edema formation.

We have previously proven the involvement of transient receptor potential ankyrin 1 (TRPA1) in stress adaptation. A lack of TRPA1 affects both urocortin 1 (member of the corticotropin-releasing hormone (CRH) family) content of the Edinger–Westphal nucleus. The noradrenergic locus ceruleus (LC) is also an important player in mood control. We aimed at investigating whether the TRPA1 is expressed in the LC, and to test if the response to chronic variable mild stress (CVMS) is affected by a lack of TRPA1. The TRPA1 expression was examined via RNAscope in situ hybridization. We investigated TRPA1 knockout and wildtype mice using the CVMS model of depression. Tyrosine hydroxylase (TH) and FOSB double immunofluorescence were used to test the functional neuromorphological changes in the LC. No TRPA1 expression was detected in the LC. The TH content was not affected by CVMS exposure. The CVMS-induced FOSB immunosignal did not co-localize with the TH neurons. TRPA1 is not expressed in the LC. A lack of functional TRPA1 receptor neither directly nor indirectly affects the TH content of LC neurons under CVMS.

Spontaneously hypertensive rats (SHR) have high sympathetic tone and progressive hypertension. Chronic calorie-restriction prevents hypertension. Their food intake (FI) and body weight are lower than in normotensive (NT) controls, even on a high-fat diet, suggesting a dysregulation of energy homeostasis. We assumed enhanced activity of hypothalamic anorexigenic melanocortins and diminished tone of orexigenic neuropeptide Y (NPY) in the background. FI of male SHR and NT Wistar rats was recorded in a FeedScale system upon intracerebroventricular injection of NPY, melanocortin ligands alpha-melanocyte-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP) or during a 7-day intracerebroventricular infusion of melanocortin antagonist HS024. Alpha-MSH, NPY, and AgRP immunoreactivities were semi-quantified in the arcuate (ARC) and paraventricular (PVN) nuclei of the hypothalamus in NT vs. SHR. Proopiomelanocortin gene expression was also assessed by quantitative RT-PCR in the ARC. Melanocortin-induced anorexia was stronger, FI induced by NPY or HS024 was smaller and delayed in SHR. Cellular alpha-MSH-specific signal density was higher in the ARC of SHR as evaluated by immunofluerescence, which was supported by PCR data. In the PVN, no differences in alpha-MSH-, NPY-, or AgRP-immunosignal were observed. Our results suggest that a higher melanocortin production/responsiveness and lower NPY responsiveness may contribute to the body weight dysregulation of SHR.

Administration of the long form (38 amino acids) of pituitary adenylate cyclase-activating polypeptide (PACAP38) into the central nervous system causes hyperthermia, suggesting that PACAP38 plays a role in the regulation of deep body temperature ( T b ). In this study, we investigated the thermoregulatory role of PACAP38 in details. First, we infused PACAP38 intracerebroventricularly to rats and measured their T b and autonomic thermoeffector responses. We found that central PACAP38 infusion caused dose-dependent hyperthermia, which was brought about by increased thermogenesis and tail skin vasoconstriction. Compared to intracerebroventricular administration, systemic (intravenous) infusion of the same dose of PACAP38 caused significantly smaller hyperthermia, indicating a central site of action. We then investigated the thermoregulatory phenotype of mice lacking the Pacap gene ( Pacap −/− ). Freely moving Pacap −/− mice had higher locomotor activity throughout the day and elevated deep T b during the light phase. When the Pacap −/− mice were loosely restrained, their metabolic rate and T b were lower compared to their wild-type littermates. We conclude that PACAP38 causes hyperthermia via activation of the autonomic cold-defense thermoeffectors through central targets. Pacap −/− mice express hyperkinesis, which is presumably a compensatory mechanism, because under restrained conditions, these mice are hypometabolic and hypothermic compared to controls.