Diabetic neuropathy (DN) affects more than 50 % of patients with diabetes mellitus (DM). With progression, it causes negative symptoms characterized by sensory numbness. However, no effective treatment drug has been appr...Diabetic neuropathy (DN) affects more than 50 % of patients with diabetes mellitus (DM). With progression, it causes negative symptoms characterized by sensory numbness. However, no effective treatment drug has been approved for the negative symptoms of DN. In this study, Stachybotrys microspora triprenyl phenol-44D (SMTP-44D), previously reported to inhibit apoptosis and ameliorate axonal damage in immortalized mouse Schwann cells treated with high glucose, was evaluated in a DN mouse model. Streptozocin (STZ)-induced DM models were treated with SMTP-44D for 49 days starting 8 days after STZ administration of SMTP-44D, and effects on mechanical and thermal thresholds, blood flow, and conduction velocity were evaluated. Epoxyeicosatrienoic acid (EET)/dihydroxyeicosatrienoic acid (DHET) measurements in serum, morphological changes in the sciatic nerve, immunohistochemistry, and TUNEL staining were performed to elucidate the mechanism of action. SMTP-44D improved the 11,12-EET/DHET decrease in serum and blood flow in the sciatic nerve. It inhibited sciatic nerve apoptosis and alleviated myelin thinning, thereby preserving the conduction velocity and showing dose-dependent improvements in mechanical and thermal threshold elevation. A hypoglycemic effect with long-term administration is suggested based on the findings. In conclusion, SMTP-44D is a promising therapeutic agent against the negative symptoms of DN.
Rodent rearing behavior is frequently assessed as an indicator of anxiety and exploratory tendencies. This study developed a convolutional recurrent neural network (CRNN) model to detect mouse rearing using overhead vide...Rodent rearing behavior is frequently assessed as an indicator of anxiety and exploratory tendencies. This study developed a convolutional recurrent neural network (CRNN) model to detect mouse rearing using overhead videos. Behavioral data from C57BL/6 mice under light and dark conditions were manually labeled frame-by-frame and used to train the CRNN model. Model performance was evaluated on separate test videos, achieving a sensitivity of 89.2 %, comparable to human observation. The model reliably detected increased rearing following caffeine administration and distinguished differences between day and night activity patterns.
Wheel running is rewarding for rodents, and thus they exhibit strong willingness to engage in it and desire for it, i.e., motivation. Although neural activity in the dorsomedial striatum (DM-Str) has been suggested to be...Wheel running is rewarding for rodents, and thus they exhibit strong willingness to engage in it and desire for it, i.e., motivation. Although neural activity in the dorsomedial striatum (DM-Str) has been suggested to be involved in motivation for wheel running, the causal relationship between neural activity and motivation remains unknown. Here, we investigated the role of neural activity in the DM-Str and the mechanisms regulating this activity in motivation for wheel running. Fiber photometry recordings with GCaMP sensors revealed that DM-Str neural activity transiently increased at the initiation of running on running wheels (RWs), whereas it decreased during running. Intra-DM-Str injection of the GABA receptor agonist muscimol or the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist NBQX reduced the number of RW rotations. In the open field test, neither muscimol nor NBQX injection into the DM-Str affected locomotor activity. Additionally, selective chemogenetic inhibition of projections from the medial prefrontal cortex (mPFC) to the DM-Str reduced RW rotation numbers without altering locomotor activity. Together, our findings suggest that DM-Str neural activity, enhanced by glutamatergic projection from the mPFC, plays a critical role in regulating motivation for wheel running.
Osteoarthritis (OA) is joint pain caused by persistent low-grade inflammation, and is characterized by bone remodeling, synovitis, and articular cartilage degeneration. This study focused on undenatured type II collagen...Osteoarthritis (OA) is joint pain caused by persistent low-grade inflammation, and is characterized by bone remodeling, synovitis, and articular cartilage degeneration. This study focused on undenatured type II collagen (UC-II®) and examined its influence on OA-associated pain. The increased Ca influx to typical nociceptive receptors TRPA1 and TRPV1 in the peripheral neurons of dorsal root ganglia was significantly inhibited by UC-II® treatment and similar inhibitory patterns were confirmed in vivo pain behavior tests in a mouse model of arthritis. Our findings suggest the effectiveness of UC-II® on OA-associated pain.
Mirabegron is the first selective β-adrenoceptor agonist, to be developed as an alternative to antimuscarinic therapy for patients with overactive bladder (OAB). This agent exerts off-target effects on muscarinic recepto...Mirabegron is the first selective β-adrenoceptor agonist, to be developed as an alternative to antimuscarinic therapy for patients with overactive bladder (OAB). This agent exerts off-target effects on muscarinic receptors. Its combination with solifenacin results in a higher incidence of anticholinergic effects, such as dry mouth, than solifenacin alone. The present study investigated whether the combination of mirabegron and antimuscarinics exerted additive effects on muscarinic receptors and cholinergic contraction in rat tissues. Muscarinic receptor binding activity and inhibitory effect on carbachol-induced contraction in rat tissues were evaluated by radioreceptor assays using [N-methyl-H]scopolamine chloride (3HNMS) and the organ-bath procedure, respectively. The muscarinic receptor binding activities of solifenacin and imidafenacin in the rat brain increased when administered in combination with mirabegron. Moreover, the inhibitory effects of solifenacin and imidafenacin on carbachol-induced contractions in rat isolated bladder strips were increased by mirabegron, particularly at lower concentrations of solifenacin and imidafenacin. This is the first study to suggest that mirabegron in combination with antimuscarinics exerts additive effects for muscarinic receptor binding and inhibitory effects on cholinergic contractions in bladder strips. The results obtained also showed that these additive effects may contribute to enhanced therapeutic effects on OAB, but also cholinergic adverse effects.
The natriuretic peptide and cyclic guanosine monophosphate (cGMP) cascade are promising therapeutic target for heart failure. This study evaluated the pharmacological properties and cardioprotective effects of novel phos...The natriuretic peptide and cyclic guanosine monophosphate (cGMP) cascade are promising therapeutic target for heart failure. This study evaluated the pharmacological properties and cardioprotective effects of novel phosphodiesterase 9 (PDE9) inhibitors, KR39526 and KR39582, in vitro and in vivo. The potency and selectivity of these compounds were assessed through PDE9 inhibitory activity and subfamily selectivity assays. Functional analyses in cardiomyocytes included calcium mobilization, cellular hypertrophy, and protein expression. The cardioprotective efficacy was investigated using a mouse model of pressure-overload-induced cardiac hypertrophy. KR39526 and KR39582 demonstrated potent PDE9A inhibitory activities (IC: 5 ± 2 nM and 0.4 ± 0.1 nM, respectively) with high selectivity. This inhibition led to concentration-dependent calcium influx through maintaining intracellular cGMP levels and significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy. Oral administration (50 mg·kg-1) of these compounds markedly attenuated cardiac hypertrophy and myocardial fibrosis induced by pressure overload. These results suggest that KR39526 and KR39582, as potent and selective PDE9A inhibitors, have strong potential for exerting anti-hypertrophic and anti-fibrotic effects in heart failure. These compounds can serve as valuable pharmacological tools to elucidate the roles of PDE9A signaling in heart failure pathophysiology and hold significant promise as potential therapeutic agents.
The inhibitory effects and underlying mechanisms of schisandrin A (SA) on contractions induced by spasmogenic candidates and related chemicals were investigated in porcine coronary arteries (PCAs). SA (10-10 M) inhibited...The inhibitory effects and underlying mechanisms of schisandrin A (SA) on contractions induced by spasmogenic candidates and related chemicals were investigated in porcine coronary arteries (PCAs). SA (10-10 M) inhibited contractions induced by acetylcholine, histamine, serotonin, U46619 (thromboxane A mimetic), prostaglandin F, and endothelin-1 in a concentration-dependent manner. The inhibition of acetylcholine-induced contractions by SA was stronger than that by diltiazem, although both SA and diltiazem ultimately achieved similar levels of inhibition against other contractions. SA also inhibited high-KCl-induced contractions in PCAs and suppressed high-KCl-induced increases in intracellular Ca concentrations in A7r5 cells. However, SA (10 M) did not inhibit SKF-96365-sensitive phenylephrine-induced contractions, despite potently inhibiting high-KCl-induced contraction in the guinea pig thoracic aorta. SA did not strongly inhibit NaF-induced contractions in Ca-free solution containing 0.2 mM EGTA. Furthermore, SA inhibited muscarinic receptor binding in mouse cerebral cortex and inhibited carbachol-induced increases in intracellular Ca concentrations in 293T cells expressing muscarinic M receptors. These findings indicate that SA inhibits coronary artery contractions induced by spasmogens primarily through the inhibition of L-type Ca channels (LCCs) and exerts an anticholinergic and LCC inhibitory effect on acetylcholine-induced contractions.
Hypoxia-inducible factor (HIF)-1α is a master transcription factor regulating hypoxic adaptation and activates the transcription of genes involved in various steps of energy metabolism. However, some subsets of cancer ce...Hypoxia-inducible factor (HIF)-1α is a master transcription factor regulating hypoxic adaptation and activates the transcription of genes involved in various steps of energy metabolism. However, some subsets of cancer cells exhibit high HIF-1α levels regardless of the oxygen concentration. Even under normoxic and normoglycemic conditions, HIF-1α regulates basal expression of its target genes. Osteoclasts are giant multinucleated cells derived from the monocyte/macrophage lineage and are specialized in bone resorption. Excessive osteoclast resorbing activities is involved in destructive bone diseases. There are few data regarding how HIF-1α affects osteoclast differentiation. In this study, we investigated whether echinomycin, a HIF-1α inhibitor, reduced the expression of proteins of aerobic glycolysis, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4), and whether HIF-1α stabilization is involved in osteoclast differentiation. HIF-1α was stabilized earlier than the upregulation of GLUT1, LDHA, and MCT4 expression during osteoclast differentiation. Echinomycin inhibited GLUT1, LDHA, and MCT4 expression. It also inhibited osteoclast differentiation and suppressed osteoclast bone-resorbing activity. We propose that HIF-1α inhibition suppresses excessive osteoclast differentiation and may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.
Serotonin neurons are central to the pathophysiology and therapeutics of mental disorders, including major depressive disorder, anxiety, and schizophrenia. Genetically modified mice make it possible to target serotonin n...Serotonin neurons are central to the pathophysiology and therapeutics of mental disorders, including major depressive disorder, anxiety, and schizophrenia. Genetically modified mice make it possible to target serotonin neurons by selective expression of the Cre and Flp genes; however, orthogonal methods that can be used in combination with Cre and Flp are of high importance, considering the highly complicated neural networks in the brain. Here, we improved serotonin neuron-specific viral vectors with higher specificity and sufficient potency for optogenetic manipulation and recording.
Liver cancer ranks as the third leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90 % of primary liver cancer cases. Elevated expression of drug-metabolizi...Liver cancer ranks as the third leading cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 90 % of primary liver cancer cases. Elevated expression of drug-metabolizing enzyme CYP1B1 in HCC has been identified as a potential contributor to primary paclitaxel (PTX) resistance. This study demonstrated that miR-200b-3p suppresses CYP1B1 expression in HCC cells. Meanwhile, miR-200b-3p was significantly downregulated in HCC tissues compared to adjacent normal tissues and negatively correlated with CYP1B1 expression. In addition, miR-200b-3p sensitized HCC to PTX in vitro and in vivo patient-derived xenograft (PDX) models by inhibiting CYP1B1, promoting PTX-induced microtubule polymerization, and enhancing its cell cycle-blocking effects. These findings indicate that miR-200b-3p could serve as a promising therapeutic strategy by directly targeting CYP1B1 in HCC.
Vascular dementia (VaD) is a leading cause of cognitive decline, closely associated with cerebrovascular endothelial cell (CEC) dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation. CD38, an enzyme im...Vascular dementia (VaD) is a leading cause of cognitive decline, closely associated with cerebrovascular endothelial cell (CEC) dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation. CD38, an enzyme implicated in neuroinflammation and cellular senescence, has emerged as a potential regulator of these pathological processes, yet its role in CEC dysfunction within the context of VaD remains unclear. In this study, we investigated the impact of CD38 on CEC dysfunction using a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Our results demonstrate that BCAS significantly reduces cerebral blood flow (CBF), increases BBB permeability, and induces cognitive deficits, all accompanied by elevated CD38 expression in CECs and heightened levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Notably, treatment with the selective CD38 inhibitor 78c (10 mg/kg, twice daily for 1 month) effectively mitigated these effects, reducing white matter damage, improving CBF, enhancing the expression of CEC tight junction proteins, and decreasing neuroinflammation and BBB disruption. In vitro experiments further revealed that 78c attenuates TNF-α-induced CD38 expression and inflammatory responses in CECs, likely through the NOX4/eNOS aixs. These findings identify CD38 as a crucial mediator of CEC dysfunction in VaD, linking chronic cerebral hypoperfusion to neurovascular damage.
Parkinson's disease (PD) is the second most prevalent idiopathic neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to locomotor impairment. Despi...Parkinson's disease (PD) is the second most prevalent idiopathic neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to locomotor impairment. Despite extensive research, the etiology of PD remains unclear, and existing experimental models for pharmacological evaluation do not fully replicate the disease's hallmarks, necessitating the development of a cost-effective and reliable alternative. In recent past, Drosophila melanogaster has been utilized as a model organism for various neurodegenerative diseases, including PD. The present study was conceptualized to develop a reliable PD model in the Drosophila by Zinc (Zn).Chronic exposure to 20 mM Zn for 7 days exhibited non-motor and motor PD-like symptoms in adult Drosophila flies, with reduced locomotory activity, indicating motor function deficit and reduced olfactory function and courtship behavior, indicating a deficit in non-motor function. These behavioral symptoms were associated with decreased dopamine levels. Furthermore, chronic Zn exposure resulted in enhanced membrane lipid peroxidation and decreased endogenous antioxidants level in the Drosophila brain. These effects were primarily mediated by oxidative/nitrosative stress pathway. Thus, Zn-induced PD in Drosophila serves as a cost-effective model for drug discovery, facilitating the screening of potential therapeutic compounds. Additionally, this model offers a valuable platform to investigate the molecular mechanisms underlying PD pathophysiology.
Post-stroke cognitive impairment (PSCI) is a clinical disorder that commonly occurs after a stroke and may persist long-term in most stroke survivors. Neuroinflammation involving proinflammatory M1 microglia, an activate...Post-stroke cognitive impairment (PSCI) is a clinical disorder that commonly occurs after a stroke and may persist long-term in most stroke survivors. Neuroinflammation involving proinflammatory M1 microglia, an activated microglial phenotype after stroke injury, is a major risk factor for PSCI. Tomatidine is a steroidal alkaloid of immature green tomatoes that has anti-inflammatory properties. To investigate the effects of tomatidine on cognitive impairment and microglial-associated neuroinflammation after stroke, we performed behavioral experiments and analyses on activated microglia in a transient bilateral common carotid arteries occlusion (tBCCAO) mouse model. Tomatidine attenuated cognitive impairment and neurodegeneration in the CA1 and CA3 hippocampal regions and reduced microglial activation and polarization into an M1 phenotype in the hippocampus in tBCCAO mice. The direct effect of tomatidine on polarization into the M1 phenotype was examined using LPS-stimulated BV2 microglia, as an M1 microglia model. Tomatidine reduced expression of M1 microglial markers and inflammatory mediators and inhibited nuclear translocation and phosphorylation of NF-κB in LPS-treated BV2 microglia. These results suggest that tomatidine suppresses microglial polarization into an M1 phenotype via modulation of NF-κB signaling, resulting in attenuation of neuroinflammation and reduction of PSCI.
We investigated the effects of ferulic acid (FA) on contractions in guinea pig ileal longitudinal smooth muscle (ILSM). FA (3 × 10-3 × 10 M) inhibited ILSM contractions induced by acetylcholine, histamine, prostaglandin...We investigated the effects of ferulic acid (FA) on contractions in guinea pig ileal longitudinal smooth muscle (ILSM). FA (3 × 10-3 × 10 M) inhibited ILSM contractions induced by acetylcholine, histamine, prostaglandin F, and serotonin concentration-dependently, reversibly, and noncompetitively with pD' values of ∼3. FA also concentration-dependently and reversibly inhibited KCl-induced ILSM contractions. FA (10 M), which inhibited ILSM contractions by ∼50 %, also reduced verapamil-sensitive, KCl-induced intracellular Ca increases in A7r5 cells by ∼35 %. These results suggest that FA inhibits ILSM contraction, primarily through the reversible inhibition of Ca influx via voltage-dependent Ca channels.
We examined whether γ-linolenic acid (GLA), an n-6 polyunsaturated fatty acid (PUFA) and a structural isomer of α-linolenic acid (an n-3 PUFA), inhibited contractions of isolated pig coronary arteries. GLA potently inhib...We examined whether γ-linolenic acid (GLA), an n-6 polyunsaturated fatty acid (PUFA) and a structural isomer of α-linolenic acid (an n-3 PUFA), inhibited contractions of isolated pig coronary arteries. GLA potently inhibited the contractions elicited by U46619/prostaglandin F, while showing marginal effects against other contractions. Schild plot analysis of GLA versus U46619 showed a competitive antagonistic effect. GLA also inhibited the intracellular Ca concentration increases caused by prostanoid TP but not by FP receptor stimulation. These results suggest that TP receptor antagonistic activity can be exhibited by non-n-3 PUFAs in coronary arteries.
The aging population has increased neurodegenerative diseases, yet current therapies mostly relieve symptoms rather than halt disease progression. Neural stem cells (NSCs) are crucial in nervous system development and re...The aging population has increased neurodegenerative diseases, yet current therapies mostly relieve symptoms rather than halt disease progression. Neural stem cells (NSCs) are crucial in nervous system development and repair, and research on their proliferation and differentiation regulation is vital. This study aimed to explore the effect of pedunculoside (PE) on primary NSCs and its mechanism. NSCs from pregnant rats (E13 - E14) were cultured and studied using CCK - 8, EDU incorporation, immunofluorescence, Western blot, and molecular docking. Results showed PE significantly promoted NSC proliferation at 10 μM and 20 μM dose - dependently. It also enhanced neuronal differentiation, with increased TUJ - 1 and decreased GFAP. Molecular docking and Western blot revealed PE binds to PI3K, activates the PI3K/AKT/GSK-3β pathway, and promotes protein phosphorylation. The PI3K inhibitor experiment confirmed PE's effect on NSC differentiation is mediated by this pathway. This study provides evidence for PE's role in NSC research and advances nervous system disease treatment research.
Eukaryotic elongation factor 2 kinase (eEF2K) is a protein kinase, regulating peptide translation. Zucker fatty diabetes mellitus (ZFDM) rat is a recently developed obesity and type 2 diabetes animal model with a missens...Eukaryotic elongation factor 2 kinase (eEF2K) is a protein kinase, regulating peptide translation. Zucker fatty diabetes mellitus (ZFDM) rat is a recently developed obesity and type 2 diabetes animal model with a missense mutation (fa) in leptin receptor gene (Lepr). ZFDM-Lepr rats (Homo) develop obesity and type 2 diabetes, while ZFDM-Lepr rats (Hetero) are normal. The aim of this study was to determine effects of A484954 on glucose metabolism in ZFDM rats. A484954 (2.5 mg/kg) or carboxymethyl cellulose (CMC; 0.5 %), a vehicle was injected intraperitoneally for 15 days in 17-19-week-old rats. Compared with Hetero CMC, in Homo CMC; 1) blood and urine glucose levels were significantly elevated, 2) Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was significantly elevated, 3) mRNA expression of sodium-glucose cotransporter (SGLT)2 in kidney tended to be elevated, while that of glucose transporter (GLUT)4 in vastus lateralis muscle decreased. Compared with Homo CMC, in Homo A484954; 1) blood glucose was significantly reduced, while urine glucose did not change, 2) HOMA-IR tended to decrease, 3) mRNA expression of SGLT2 in the kidney and GLUT4 in the muscle did not change. This study demonstrates for the first time that A484954 induces hypoglycemic effects in Homo partly via preventing insulin resistance.
Kamishoyosan (KSS) is a well-known traditional Japanese herbal medicine used to treat psychiatric symptoms, such as irritation. We previously reported that KSS decreases mouse aggressive biting behavior (ABB) to inanimat...Kamishoyosan (KSS) is a well-known traditional Japanese herbal medicine used to treat psychiatric symptoms, such as irritation. We previously reported that KSS decreases mouse aggressive biting behavior (ABB) to inanimate objects using the Aggression Response Meter, however, it was not revealed which ingredient of KSS is effective. In this study, we used real-time reverse transcriptase (RT) PCR to investigate the mRNA expression of 5-HT-related genes in SH-SY5Y cells cultured in a medium containing the ten individual herbal medicines in KSS. The cells treated with shakuyaku showed increase of tryptophan hydroxylase mRNA expression, whereas those cultured in a medium containing botanpi showed decreased monoamine oxidase A and B mRNA levels. We investigated the ABB of mice administered with Paeonia lactiflora (shakuyaku) or Paeonia suffruticosa (botanpi). We also examined the gene expression in cells treated with paeoniflorin (PF), a main active component in shakuyaku, and the ABB of PF-treated mice. We found that shakuyaku or PF administration reduced ABB in male and female mice, whereas botanpi treatment mitigated ABB only in males. WAY-100635, a 5-HT1A receptor antagonist, abolished ABB-reducing effect of shakuyaku and botanpi. These results suggest that shakuyaku and botanpi are activate ingredient to reduce ABB through activation on serotoninergic neurotransmission.
The ability to target the oxytocin and vasopressin receptors is of high therapeutic value due to their clinical relevance in wide range of neuropsychiatric conditions spanning from anxiety to schizophrenia. Despite the m...The ability to target the oxytocin and vasopressin receptors is of high therapeutic value due to their clinical relevance in wide range of neuropsychiatric conditions spanning from anxiety to schizophrenia. Despite the massive therapeutic potential in modulating this system, the only clinically approved small molecule-based therapeutics (Mozavaptan, Conivaptan and Tolvaptan) are for use in the periphery. Cyclotide mimetics of the native neuropeptides are well explored in the literature although these scaffolds are unsuitable for application to the central nervous system. This work highlights non-peptidic natural products that are active within the neurohypophysial system that may be used to inspire future drug discovery endeavours.
Prostaglandin E (PGE) facilitates the micturition reflex at the lower urinary tract and spinal cord levels. However, the roles of brain PGE in reflex regulation remain unclear. Therefore, we aimed to investigate the effe...Prostaglandin E (PGE) facilitates the micturition reflex at the lower urinary tract and spinal cord levels. However, the roles of brain PGE in reflex regulation remain unclear. Therefore, we aimed to investigate the effects of intracerebroventricularly administered PGE on the micturition reflex. We further investigated whether the PGE-induced responses were dependent on the sympathetic nervous system (SNS) and identified the brain E-prostanoid receptor subtypes (EP-EP) involved in PGE-induced effects. Intracerebroventricularly administered PGE (0.1, 0.3, or 1 nmol/rat) dose-dependently increased the intercontraction intervals (ICI) and threshold pressure required to induce micturition (TP) without altering maximal voiding pressure in urethane-anesthetized (0.8 g/kg, ip) male rats. PGE (1 nmol/rat) significantly increased the mean blood pressure; 6-hydroxydopamine-induced chemical sympathectomy ameliorated this increase. In contrast, chemical sympathectomy had no significant effect on the PGE-induced increases in ICI and TP. Intracerebroventricularly pretreated SC51322 (EP receptor antagonist, 100 nmol/rat) and PF04418948 (EP receptor antagonist, 100 nmol/rat), but not L-798106 (EP receptor antagonist, 100 nmol/rat) or L-161982 (EP receptor antagonist, 100 nmol/rat), significantly attenuated the PGE (1 nmol/rat)-induced changes in ICI and TP. These results suggest that centrally administered PGE suppresses the rat micturition reflex through brain EP and EP receptors, independent of SNS activation.