Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats.

Introduction: Within the realm of chemogenetics, a particular form of agonists targeting designer receptors exclusively activated by designer drugs (DREADDs) has emerged. Deschloroclozapine (DCZ), a recently introduced DREADDs agonist, demonstrates remarkable potency in activating targeted neurons at a lower dosage compared to clozapine-N-oxide (CNO). Methods: We conducted a comparative analysis of the effects of subcutaneously administered CNO (1 mg/kg) and DCZ (0.1 mg/kg) in our transgenic rats expressing hM3Dq and mCherry exclusively in oxytocin (OXT) neurons. Results and Discussion: Notably, DCZ exhibited a swift and robust elevation of serum OXT, surpassing the effects of CNO, with a significant increase in the area under the curve (AUC) up to 3 hours post-administration. Comprehensive assessment of brain neuronal activity, using Fos as an indicator, revealed comparable effects between CNO and DCZ. Additionally, in a neuropathic pain model, both CNO and DCZ increased the mechanical nociceptive and thermal thresholds; however, the DCZ-treated group exhibited a significantly accelerated onset of the effects, aligning harmoniously with the observed alterations in serum OXT concentration following DCZ administration. These findings emphasize the remarkable efficacy of DCZ in rats, suggesting its equivalent or potentially superior performance to CNO at considerably lower dosages, thus positioning it as a promising contender among DREADDs agonists.

Phase-shifting the circadian glucocorticoid profile induces disordered feeding behaviour by dysregulating hypothalamic neuropeptide gene expression.

Here we demonstrate, in rodents, how the timing of feeding behaviour becomes disordered when circulating glucocorticoid rhythms are dissociated from lighting cues; a phenomenon most commonly associated with shift-work and transmeridian travel 'jetlag'. Adrenalectomized rats are infused with physiological patterns of corticosterone modelled on the endogenous adrenal secretory profile, either in-phase or out-of-phase with lighting cues. For the in-phase group, food intake is significantly greater during the rats' active period compared to their inactive period; a feeding pattern similar to adrenal-intact control rats. In contrast, the feeding pattern of the out-of-phase group is significantly dysregulated. Consistent with a direct hypothalamic modulation of feeding behaviour, this altered timing is accompanied by dysregulated timing of anorexigenic and orexigenic neuropeptide gene expression. For Neuropeptide Y (Npy), we report a glucocorticoid-dependent direct transcriptional regulation mechanism mediated by the glucocorticoid receptor (GR). Taken together, our data highlight the adverse behavioural outcomes that can arise when two circadian systems have anti-phasic cues, in this case impacting on the glucocorticoid-regulation of a process as fundamental to health as feeding behaviour. Our findings further highlight the need for development of rational approaches in the prevention of metabolic dysfunction in circadian-disrupting activities such as transmeridian travel and shift-work.

Chemogenetic Activation of Oxytocin Neurons Improves Pain in a Reserpine-induced Fibromyalgia Rat Model.

Fibromyalgia (FM) is a syndrome characterized by chronic pain with depression as a frequent comorbidity. However, efficient management of the pain and depressive symptoms of FM is lacking. Given that endogenous oxytocin (OXT) contributes to the regulation of pain and depressive disorders, herein, we investigated the role of OXT in an experimental reserpine-induced FM model. In FM model, OXT-monomeric red fluorescent protein 1 (OXT-mRFP1) transgenic rats exhibited increased depressive behavior and sensitivity in a mechanical nociceptive test, suggesting reduced pain tolerance. Additionally, the development of the FM-like phenotype in OXT-mRFP1 FM model rats was accompanied by a significant reduction in OXT mRNA expression in the magnocellular neurons of the paraventricular nucleus. OXT-mRFP1 FM model rats also had significantly fewer tryptophan hydroxylase (TPH)- and tyrosine hydroxylase (TH)-immunoreactive (ir) neurons as well as reduced serotonin and norepinephrine levels in the dorsal raphe and locus coeruleus. To investigate the effects of stimulating the endogenous OXT pathway, rats expressing OXT-human muscarinic acetylcholine receptor (hM3Dq)-mCherry designer receptors exclusively activated by designer drugs (DREADDs) were also assessed in the FM model. Treatment of these rats with clozapine-N-oxide (CNO), an hM3Dq-activating drug, significantly improved characteristic FM model-induced pathophysiological pain, but did not alter depressive-like behavior. The chemogenetically induced effects were reversed by pre-treatment with an OXT receptor antagonist, confirming the specificity of action via the OXT pathway. These results indicate that endogenous OXT may have analgesic effects in FM, and could be a potential target for effective pain management strategies for this disorder.

Circadian regulation of hippocampal function is disrupted with corticosteroid treatment.

Disrupted circadian activity is associated with many neuropsychiatric disorders. A major coordinator of circadian biological systems is adrenal glucocorticoid secretion which exhibits a pronounced preawakening peak that regulates metabolic, immune, and cardiovascular processes, as well as mood and cognitive function. Loss of this circadian rhythm during corticosteroid therapy is often associated with memory impairment. Surprisingly, the mechanisms that underlie this deficit are not understood. In this study, in rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity processes via an intrahippocampal circadian transcriptional clock. Further, these circadian hippocampal functions were significantly impacted by corticosteroid treatment delivered in a 5-d oral dosing treatment protocol. Rhythmic expression of the hippocampal transcriptome, as well as the circadian regulation of synaptic plasticity, was misaligned with the natural light/dark circadian-entraining cues, resulting in memory impairment in hippocampal-dependent behavior. These findings provide mechanistic insights into how the transcriptional clock machinery within the hippocampus is influenced by corticosteroid exposure, leading to adverse effects on critical hippocampal functions, as well as identifying a molecular basis for memory deficits in patients treated with long-acting synthetic corticosteroids.

Endogenous oxytocin exerts anti-nociceptive and anti-inflammatory effects in rats.

Oxytocin is involved in pain transmission, although the detailed mechanism is not fully understood. Here, we generate a transgenic rat line that expresses human muscarinic acetylcholine receptors (hM3Dq) and mCherry in oxytocin neurons. We report that clozapine-N-oxide (CNO) treatment of our oxytocin-hM3Dq-mCherry rats exclusively activates oxytocin neurons within the supraoptic and paraventricular nuclei, leading to activation of neurons in the locus coeruleus (LC) and dorsal raphe nucleus (DR), and differential gene expression in GABA-ergic neurons in the L5 spinal dorsal horn. Hyperalgesia, which is robustly exacerbated in experimental pain models, is significantly attenuated after CNO injection. The analgesic effects of CNO are ablated by co-treatment with oxytocin receptor antagonist. Endogenous oxytocin also exerts anti-inflammatory effects via activation of the hypothalamus-pituitary-adrenal axis. Moreover, inhibition of mast cell degranulation is found to be involved in the response. Taken together, our results suggest that oxytocin may exert anti-nociceptive and anti-inflammatory effects via both neuronal and humoral pathways.

Oestrogen-dependent hypothalamic oxytocin expression with changes in feeding and body weight in female rats.

Oxytocin (OXT) is produced in the hypothalamic nuclei and secreted into systemic circulation from the posterior pituitary gland. In the central nervous system, OXT regulates behaviours including maternal and feeding behaviours. Our aim is to evaluate whether oestrogen regulates hypothalamic OXT dynamics. Herein, we provide the first evidence that OXT dynamics in the hypothalamus vary with sex and that oestrogen may modulate dynamic changes in OXT levels, using OXT-mRFP1 transgenic rats. The fluorescence intensity of OXT-mRFP1 and expression of the OXT and mRFP1 genes in the hypothalamic nuclei is highest during the oestrus stage in female rats and decreased significantly in ovariectomised rats. Oestrogen replacement caused significant increases in fluorescence intensity and gene expression in a dose-related manner. This is also demonstrated in the rats' feeding behaviour and hypothalamic Fos neurons using cholecystokinin-8 and immunohistochemistry. Hypothalamic OXT expression is oestrogen-dependent and can be enhanced centrally by the administration of oestrogen.

Expression of oxytocin in hypothalamus and reduction of nociceptive stress following administration of Kamikihi-to in female rats.

Hypothalamo-neurohypophysial oxytocin (OXT) plays an essential role in reproduction and in several socio-physiological functions, including stress reduction, anxiety relief, feeding suppression, social recognition, and trust building. Recent studies suggest that the central OXT system is also involved in antinociceptive and anti-inflammatory functions. Kamikihi-to (KKT), a Japanese traditional herbal (Kampo) medicine composed of 14 herbal ingredients, is clinically prescribed for patients with psychological symptoms, including anxiety, depression, and insomnia, and it has been associated with OXT expression. We investigated the antinociceptive response and OXT expression according to sex and the effects of KKT pre administration in a rat model. We found that nociceptive responses measured via the hot plate and formalin tests were attenuated following the administration of KKT-enriched feed for 4 weeks. The observation of mRFP1 fluorescence in OXT-mRFP1 transgenic rats revealed that KKT-administered rats showed increased expression of OXT in the magnocellular and parvocellular paraventricular nucleus of the hypothalamus. Food intake in the KKT-pre-administered group significantly decreased after cholecystokinin (CCK)-8 administration. Our results suggest that KKT is involved in the attenuation of nociceptive stress in female rats by enhancing the expression of OXT in the hypothalamus.

Upregulation of the hypothalamo-neurohypophysial system and activation of vasopressin neurones attenuates hyperalgesia in a neuropathic pain model rat.

Arginine vasopressin (AVP) is a hypothalamic neurosecretory hormone well known as an antidiuretic, and recently reported to be involved in pain modulation. The expression kinetics of AVP and its potential involvement in the descending pain modulation system (DPMS) in neuropathic pain (NP) remains unclear. We investigated AVP expression and its effects on mechanical and thermal nociceptive thresholds using a unilateral spinal nerve ligation (SNL) model. All rats with SNL developed NP. Intensities of enhanced green fluorescent protein (eGFP) in the supraoptic and paraventricular nuclei, median eminence, and posterior pituitary were significantly increased at 7 and 14 days post-SNL in AVP-eGFP rats. In situ hybridisation histochemistry revealed significantly increased AVP mRNA expression at 14 days post-SNL compared with the sham control group. The chemogenetic activation of AVP neurones significantly attenuated mechanical and thermal hyperalgesia with elevated plasma AVP concentration. These analgesic effects were suppressed by pre-administration with V1a receptor antagonist. AVP neurones increased the neuronal activity of serotonergic dorsal raphe, noradrenergic locus coeruleus, and inhibitory interneurones in the spinal dorsal horn. These results suggest that the hypothalamo-neurohypophysial system of AVP is upregulated in NP and activated endogenous AVP exerts analgesic effects via the V1a receptors. AVP neurones may activate the DPMS.

AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.

Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.

Impact of the relationship between hemoglobin levels and renal interstitial fibrosis on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy.

BACKGROUND: Progression of renal anemia has been shown to be associated with advanced renal tubulointerstitial lesions. This retrospective study investigated the impact of lower hemoglobin (Hb) levels and renal interstitial fibrosis and tubular atrophy (IFTA) on long-term outcomes in type 2 diabetes with biopsy-proven diabetic nephropathy. METHODS: A total of 233 patients were enrolled. The severity of IFTA was scored according to the classification by the Renal Pathology Society. Patients were stratified according to baseline Hb tertiles by IFTA status. The outcomes were the first occurrence of renal events (requirement for dialysis or 50 % decline in estimated glomerular filtration rate from baseline) and all-cause mortality. RESULTS: At baseline, 151 patients had severe IFTA. There were no patients who have been received erythropoiesis-stimulating agents at the time of renal biopsy. The severity of IFTA was the independent pathological factor of lower Hb levels. During the mean follow-up period of 8.6 years (maximum, 32.4 years), 119 renal events and 42 deaths were observed. Compared with the combined influence of the highest tertile of Hb and mild IFTA, the risks of renal events were higher for the middle tertile and for the lowest tertile of Hb in severe IFTA, whereas the risk of renal events was higher for the lowest tertile of Hb in mild IFTA. The risk of mortality was higher for the lowest tertile of Hb only in severe IFTA. There were significant interactions of tertile of Hb and IFTA in renal events and mortality. CONCLUSIONS: Impacts of lower Hb levels on long-term outcomes of diabetic nephropathy were greater in severe IFTA than in mild IFTA.

Chemogenetic activation of endogenous arginine vasopressin exerts anorexigenic effects via central nesfatin-1/NucB2 pathway.

We examined whether the chemogenetic activation of endogenous arginine vasopressin (AVP) affects central nesfatin-1/NucB2 neurons, using a transgenic rat line that was previously generated. Saline (1 mL/kg) or clozapine-N-oxide (CNO, 1 mg/mL/kg), an agonist for hM3Dq, was subcutaneously administered in adult male AVP-hM3Dq-mCherry transgenic rats (300-370 g). Food and water intake were significantly suppressed after subcutaneous (s.c.) injection of CNO, with aberrant circadian rhythmicity. The percentages of Fos expression in nesfatin-1/NucB2-immunoreactive neurons were significantly increased in the hypothalamus and brainstem at 120 min after s.c. injection of CNO. Suppressed food intake that was induced by chemogenetic activation of endogenous AVP was ablated after intracerebroventricularly administered nesfatin-1/NucB2-neutralizing antibody in comparison with vehicle, without any alteration of water intake nor circadian rhythmicity. These results suggest that chemogenetic activation of endogenous AVP affects, at least in part, central nesfatin-1/NucB2 neurons and may exert anorexigenic effects in the transgenic rats.

Arginine vasopressin: Direct and indirect action on metabolism.

From its identification and isolation in 1954, arginine vasopressin (AVP) has attracted attention, not only for its peripheral functions such as vasoconstriction and reabsorption of water from kidney, but also for its central effects. As there is now considerable evidence that AVP plays a crucial role in feeding behavior and energy balance, it has become a promising therapeutic target for treating obesity or other obesity-related metabolic disorders. However, the underlying mechanisms for AVP regulation of these central processes still remain largely unknown. In this review, we will provide a brief overview of the current knowledge concerning how AVP controls energy balance and feeding behavior, focusing on physiological aspects including the relationship between AVP, circadian rhythmicity, and glucocorticoids.

Heat hypersensitivity is attenuated with altered expression level of spinal astrocytes after sciatic nerve injury in TRPV1 knockout mice.

Transient receptor potential vanilloid 1 (TRPV1) modulates pain. Studies have indicated that TRPV1 is upregulated in the spinal dorsal horn in the neuropathic pain model, but its mechanism is unknown. Here, we examined the mechanism by which TRPV1 modulates neuropathic pain by employing partial sciatic nerve ligation (pSNL) in adult male C57BL/6 J (wild-type: WT) and TRPV1 knockout (Trpv1-/-) mice. We analyzed mechanical/heat sensitivities (von Frey test/hot plate test) and glial/neuronal activities (Iba-1/GFAP/FosB by immunofluorescence) in laminae I and II in the L5 ipsilateral dorsal horn of the spinal cord. Mechanical/heat sensitivities, expression levels of microglial Iba-1 and astrocytic GFAP, and the number of FosB-positive neurons were significantly increased on days 7 and 14 in the pSNL group compared with the sham-operated and non-operated groups of both WT and Trpv1-/- mice. While mechanical sensitivity was comparable between WT and Trpv1-/- mice, the threshold against heat sensitivity was markedly prolonged in Trpv1-/- than WT mice on day 14 after pSNL. Conversely, the increment of FosB positive neurons was significantly attenuated in Trpv1-/- than WT mice on days 7 and 14 after pSNL. These results suggest that TRPV1 may modulate thermal perception via increased astrocytes in the dorsal horn of the spinal cord.

Induction of Fos expression in the rat brain after intragastric administration of dried bonito dashi.

Objectives: Dried bonito dashi, a traditional Japanese fish broth made from dried bonito tuna, enhances food palatability due to its specific umami flavor characteristics. However, the pattern of brain activation following dashi ingestion has not been previously investigated.Methods: We mapped activation sites of the rat brain after intragastric loads of dried bonito dashi by measuring neuronal levels of the Fos protein, a functional marker of neuronal activation.Results: Compared to intragastric saline, intragastric dashi administration produced enhanced Fos expression in four forebrain regions: the medial preoptic area, subfornical organ, habenular nucleus, and central nucleus of the amygdala. Interestingly, the medial preoptic area was found to be the only feeding-related hypothalamic area responsive to dashi administration. Moreover, dashi had no effect in the nucleus accumbens and ventral tegmental area, two connected sites known to be activated by highly palatable sugars and fats. In the hindbrain, dashi administration produced enhanced Fos expression in both visceral sensory (caudal nucleus of the solitary tract, dorsal part of the lateral parabrachial nucleus, and area postrema) and autonomic (rostral ventrolateral medulla, and caudal ventrolateral medulla) sites.Discussion: The results demonstrate the activation of discrete forebrain and hindbrain regions following intragastric loads of dried bonito dashi. Our data suggest that the gut-brain axis is the principal mediator of the postingestive effects associated with the ingestion of dashi.

Oxytocin-monomeric red fluorescent protein 1 synthesis in the hypothalamus under osmotic challenge and acute hypovolemia in a transgenic rat line.

We generated a transgenic rat line that expresses oxytocin (OXT)-monomeric red fluorescent protein 1 (mRFP1) fusion gene to visualize the dynamics of OXT. In this transgenic rat line, hypothalamic OXT can be assessed under diverse physiological and pathophysiological conditions by semiquantitative fluorometry of mRFP1 fluorescence intensity as a surrogate marker for endogenous OXT. Using this transgenic rat line, we identified the changes in hypothalamic OXT synthesis under various physiological conditions. However, few reports have directly examined hypothalamic OXT synthesis under hyperosmolality or hypovolemia. In this study, hypothalamic OXT synthesis was investigated using the transgenic rat line after acute osmotic challenge and acute hypovolemia induced by intraperitoneal (i.p.) administration of 3% hypertonic saline (HTN) and polyethylene glycol (PEG), respectively. The mRFP1 fluorescence intensity in the paraventricular (PVN) and supraoptic nuclei (SON) was significantly increased after i.p. administration of HTN and PEG, along with robust Fos-like immunoreactivity (co-expression). Fos expression showed neuronal activation in the brain regions that are associated with the hypothalamus and/or are involved in maintaining water and electrolyte homeostasis in HTN- and PEG-treated rats. OXT and mRFP1 gene expressions were dramatically increased after HTN and PEG administration. The plasma OXT level was extremely increased after HTN and PEG administration. Acute osmotic challenge and acute hypovolemia induced upregulation of hypothalamic OXT in the PVN and SON. These results suggest that not only endogenous arginine vasopressin (AVP) but also endogenous OXT has a key role in maintaining body fluid homeostasis to cope with hyperosmolality and hypovolemia.

The neurohypophysial oxytocin and arginine vasopressin system is activated in a knee osteoarthritis rat model.

Osteoarthritis (OA) causes chronic joint pain and significantly impacts daily activities. Hence, developing novel treatment options for OA has become an increasingly important area of research. Recently, studies have reported that exogenous, as well as endogenous, hypothalamic-neurohypophysial hormones, oxytocin (OXT) and arginine-vasopressin (AVP), significantly contribute to nociception modulation. Moreover, the parvocellular OXT neurone (parvOXT) extends its projection to the superficial spinal dorsal horn, where it controls the transmission of nociceptive signals. Meanwhile, AVP produced in the magnocellular AVP neurone (magnAVP) is released into the systemic circulation where it contributes to pain management at peripheral sites. The parvocellular AVP neurone (parvAVP), as well as corticotrophin-releasing hormone (CRH), suppresses inflammation via activation of the hypothalamic-pituitary adrenal (HPA) axis. Previously, we confirmed that the OXT/AVP system is activated in rat models of pain. However, the roles of endogenous hypothalamic-neurohypophysial hormones in OA have not yet been characterised. In the present study, we investigated whether the OXT/AVP system is activated in a knee OA rat model. Our results show that putative parvOXT is activated and the amount of OXT-monomeric red fluorescent protein 1 positive granules in the ipsilateral superficial spinal dorsal horn increases in the knee OA rat. Furthermore, both magnAVP and parvAVP are activated, concurrent with HPA axis activation, predominantly modulated by AVP, and not CRH. The OXT/AVP system in OA rats was similar to that in systemic inflammation models, including adjuvant arthritis; however, magnocellular OXT neurones (magnOXT) were not activated in OA. Hence, localised chronic pain conditions, such as knee OA, activate the OXT/AVP system without impacting magnOXT.

Peripherally administered cisplatin activates a parvocellular neuronal subtype expressing arginine vasopressin and enhanced green fluorescent protein in the paraventricular nucleus of a transgenic rat.

Cisplatin is one of the most potent anti-cancer drugs, though several side effects can induce stress responses such as activation of the hypothalamic-pituitary adrenal (HPA) axis. Arginine vasopressin (AVP) and corticotrophin-releasing hormone (CRH) expressed in the parvocellular division of the paraventricular nucleus (pPVN) play an important role in the stress-induced activation of the HPA axis. We aimed to evaluate whether intraperitoneal (i.p.) administration of cisplatin could activate parvocellular neurons in the pPVN, using a transgenic rat model that expresses the fusion gene of AVP and enhanced green fluorescent protein (eGFP). Along with the induction of FosB, a marker of neuronal activation, i.p. administration of cisplatin significantly increased eGFP fluorescent intensities in the pPVN. In situ hybridization histochemistry revealed that AVP-eGFP and CRH mRNAs in the pPVN were increased significantly in cisplatin-treated rats. These results suggest that cisplatin administration increases neuronal activation and upregulates AVP and CRH expression in the pPVN.

Expression of hypothalamic feeding-related peptide genes and neuroendocrine responses in an experimental allergic encephalomyelitis rat model.

Experimental allergic encephalomyelitis (EAE) is considered to be a useful animal model of human multiple sclerosis (MS). However, among the various symptoms of MS, the mechanisms contributing to inflammatory anorexia remain unclear. In the present study, we used an EAE rat model to examine changes in expression levels of hypothalamic feeding-related peptide genes and neuroendocrine responses such as the hypothalamo-neurohypophysial system and the hypothalamo-pituitary-adrenal (HPA) axis. The weight gain and cumulative food intake in EAE rats in the early days after immunization was significantly lower than that of the control group. The expression of orexigenic peptide genes Npy and Agrp were significantly increased, whereas the levels of anorectic peptide genes (Pomc and Cart) were significantly decreased in the hypothalamus of EAE rats. There was also a significant increase in the mRNA and plasma oxytocin (OXT) but not of arginine vasopressin (AVP) in the supraoptic and paraventricular nuclei (PVN) of EAE rats at days 12 and 18 after immunization. The expression of corticotropin-releasing hormone (Crh) and Avp was downregulated and upregulated, respectively, in the parvocellular division of the PVN at day 12 after immunization. The expression level of Pomc in the anterior pituitary significantly increased, accompanied by increased plasma corticosterone levels, at days 6, 12, and 18 after immunization. These results suggest that inflammatory anorexia in rat EAE may be caused by activation of the OXT-ergic pathway and HPA axis via changes in the expression of hypothalamic feeding-related peptides, including Avp but not Crh.

Acute Mono-Arthritis Activates the Neurohypophysial System and Hypothalamo-Pituitary Adrenal Axis in Rats.

Various types of acute/chronic nociceptive stimuli cause neuroendocrine responses such as activation of the hypothalamo-neurohypophysial [oxytocin (OXT) and arginine vasopressin (AVP)] system and hypothalamo-pituitary adrenal (HPA) axis. Chronic multiple-arthritis activates the OXT/AVP system, but the effects of acute mono-arthritis on the OXT/AVP system in the same animals has not been simultaneously evaluated. Further, AVP, not corticotropin-releasing hormone (CRH), predominantly activates the HPA axis in chronic multiple-arthritis, but the participation of AVP in HPA axis activation in acute mono-arthritis remains unknown. Therefore, we aimed to simultaneously evaluate the effects of acute mono-arthritis on the activity of the OXT/AVP system and the HPA axis. In the present study, we used an acute mono-arthritic model induced by intra-articular injection of carrageenan in a single knee joint of adult male Wistar rats. Acute mono-arthritis was confirmed by a significant increase in knee diameter in the carrageenan-injected knee and a significant decrease in the mechanical nociceptive threshold in the ipsilateral hind paw. Immunohistochemical analysis revealed that the number of Fos-immunoreactive (ir) cells in the ipsilateral lamina I-II of the dorsal horn was significantly increased, and the percentage of OXT-ir and AVP-ir neurons expressing Fos-ir in both sides of the supraoptic (SON) and paraventricular nuclei (PVN) was increased in acute mono-arthritic rats. in situ hybridization histochemistry revealed that levels of OXT mRNA and AVP hnRNA in the SON and PVN, CRH mRNA in the PVN, and proopiomelanocortin mRNA in the anterior pituitary were also significantly increased in acute mono-arthritic rats. Further, plasma OXT, AVP, and corticosterone levels were significantly increased in acute mono-arthritic rats. These results suggest that acute mono-arthritis activates ipsilateral nociceptive afferent pathways at the spinal level and causes simultaneous and integrative activation of the OXT/AVP system. In addition, the HPA axis is activated by both AVP and CRH in acute mono-arthritis with a distinct pattern compared to that in chronic multiple-arthritis.

Safety and tolerability of sifalimumab, an anti-interferon-α monoclonal antibody, in Japanese patients with systemic lupus erythematosus: A multicenter, phase 2, open-label study.

Objectives: To evaluate the safety of sifalimumab in Japanese patients with systemic lupus erythematosus (SLE).Methods: This phase 2, open-label study consisted of a 52-week initial stage (Stage I) and a long-term extension (Stage II). In Stage I, sequential cohorts of patients received ascending doses of sifalimumab (intravenous [IV] 1.0, 3.0, and 10.0 mg/kg or subcutaneous 100 mg every 2 weeks; IV 600 and 1200 mg every 6 weeks). In Stage II, patients enrolled before June 2012 received the same dose of sifalimumab as during Stage I for up to 157 weeks or sifalimumab 600 mg IV every 4 weeks if they enrolled later. The safety of sifalimumab was assessed by adverse events (AEs).Results: Thirty patients enrolled in Stage I and 21 patients entered Stage II. The majority of patients experienced AEs (96.7% in Stage I and 100% in Stage II); most were mild or moderate in severity. Serious AEs occurred in 30.0% and 57.1% of patients in Stage I and II, respectively; most were instances of SLE flares. The proportion of patients in Stage I and II who had AEs leading to discontinuation was 10.0% and 28.6%, respectively.Conclusion: Sifalimumab was well tolerated in Japanese patients with SLE.