Purinergic inhibitory regulation of esophageal smooth muscle is mediated by P2Y receptors and ATP-dependent potassium channels in rats.

Purines such as ATP are regulatory transmitters in motility of the gastrointestinal tract. The aims of this study were to propose functional roles of purinergic regulation of esophageal motility. An isolated segment of the rat esophagus was placed in an organ bath, and mechanical responses were recorded using a force transducer. Exogenous application of ATP (10-100 µM) evoked relaxation of the esophageal smooth muscle in a longitudinal direction under the condition of carbachol (1 µM) -induced precontraction. Pretreatment with a non-selective P2 receptor antagonist, suramin (500 µM), and a P2Y receptor antagonist, cibacron blue F3GA (200 µM), inhibited the ATP (100 µM) -induced relaxation, but a P2X receptor antagonist, pyridoxal phosphate-6-azophenyl-2,4-disulfonic acid (50 µM), did not affect it. A blocker of ATP-dependent potassium channels (KATP channels), glibenclamide (200 µM), inhibited the ATP-induced relaxation and application of an opener of KATP channels, nicorandil (50 µM), produced relaxation. The findings suggest that ATP is involved in inhibitory regulation of the longitudinal smooth muscle in the muscularis mucosae of the rat esophagus via activation of P2Y receptors and then opening of KATP channels.

Alterations in descending brain-spinal pathways regulating colorectal motility in a rat model of Parkinson's disease.

Patients with Parkinson's disease (PD) often have constipation. It is assumed that a disorder of the regulatory mechanism of colorectal motility by the central nervous system is involved in the constipation, but this remains unclear. The aim of this study was to investigate whether central neural pathways can modulate colorectal motility in a rat model of PD. PD model rats were generated by injection of 6-hydroxydopamine into a unilateral medial forebrain bundle and destruction of dopaminergic neurons in the substantia nigra. Colorectal motility was measured in vivo in anesthetized rats. Intraluminal administration of capsaicin, as a noxious stimulus, induced colorectal motility in sham-operated rats but not in PD rats. Intrathecally administered dopamine (DA) and serotonin (5-HT), which mediate the prokinetic effect of capsaicin, at the L6-S1 levels enhanced colorectal motility in PD rats similarly to that in sham-operated rats. In PD rats, capsaicin enhanced colorectal motility only when a GABAA receptor antagonist was preadministered into the lumbosacral spinal cord. Capsaicin-induced colorectal motility was abolished by intrathecal administration of a D2-like receptor antagonist but not by administration of 5-HT2 and 5-HT3 receptor antagonists. These findings demonstrate that the inhibitory GABAergic component becomes operative and the stimulatory serotonergic component is suppressed in PD rats. The alteration of the central regulatory mechanism of colorectal motility is thought to be related to the occurrence of constipation in PD patients. Our findings provide a new insight into the pathogenesis of defecation disorders observed in PD.NEW & NOTEWORTHY In a rat model of Parkinson's disease, the component of descending brain-spinal pathways that regulate colorectal motility through a mediation of the lumbosacral defecation center was altered from stimulatory serotonergic neurons to inhibitory GABAergic neurons. Our findings suggest that chronic constipation in Parkinson's disease patients may be associated with alterations in central regulatory mechanisms of colorectal motility. The plasticity in the descending pathway regulating colorectal motility may contribute to other disease-related defecation abnormalities.

Suncus murinus as a novel model animal that is suitable for elucidating the mechanism of daily torpor.

Torpor, a state of lowered body temperature due to active reduction of the metabolic rate, has potential medical benefits. The aim of this study was to establish a novel laboratory animal that enter torpor without imposing complex conditions. When house musk shrews (Suncus murinus) were kept at an ambient temperature of 24°C, most of the animals did not enter daily torpor. However, when the ambient temperature was lowered to below 20°C, all of the shrews showed torpor in the absence of fasting and short-day photoperiod. The shrews that were exposed to a stepwise decrease in ambient temperature from 24°C to 8°C entered torpor even after returning them to a room kept at 24°C. In conclusion, this study indicates that Suncus murinus may be a suitable model animal for elucidating the mechanism of daily torpor. Elucidation of the mechanisms of torpor by using this model may be useful for inducing a state of artificial hibernation in various species including humans.

Successful induction of deep hypothermia by isoflurane anesthesia and cooling in a non-hibernator, the rat.

The aim of the present study was to establish a novel method for inducing deep hypothermia in rats. Cooling rats anesthetized with isoflurane caused a time-dependent decrease in rectal temperature, but cardiac arrest occurred before their body temperature reached 20 °C when isoflurane inhalation was continued during the cooling process. Stopping inhalation of isoflurane when the rectal temperature reached 22.5 °C successfully induced deep hypothermia, although stopping the inhalation at 27.5 °C resulted in spontaneous recovery of rectal temperature. The hypothermic condition was able to be maintained for up to 6 h. A large number of c-Fos-positive cells were detected in the hypothalamus during hypothermia. Both the maintenance of and recovery from hypothermia caused organ injury, but the damage was transient and recovered within 1 week. These findings indicate that the established procedure is appropriate for inducing deep hypothermia without accompanying serious organ injury in rats.

Sexually dimorphic response of colorectal motility to noxious stimuli in the colorectum in rats.

KEY POINTS: This study showed a remarkable sex difference in responses of colorectal motility to noxious stimuli in the colorectum in rats: colorectal motility was enhanced in response to intracolonic administration of a noxious stimulant, capsaicin, in male rats but not in female rats. The difference in descending neurons from the brain to spinal cord operating after noxious stimulation could be responsible for the sex difference. In male rats, serotoninergic and dopaminergic neurons are dominantly activated, both of which activate the spinal defaecation centre. In female rats, GABAergic neurons in addition to serotoninergic neurons are activated. GABA may compete for facilitative action of 5-HT in the spinal defaecation centre, and thereby colorectal motility is not enhanced in response to intracolonic administration of capsaicin. The findings provide a novel insight into pathophysiological mechanisms of sex differences in functional defaecation disorders such as irritable bowel syndrome. ABSTRACT: We previously demonstrated that noxious stimuli in the colorectum enhance colorectal motility through activation of descending pain inhibitory pathways in male rats. It can be expected that the regulatory mechanisms of colorectal motility differ in males and females owing to remarkable sex differences in descending pain inhibitory pathways. Thus, we aimed to clarify sex differences in responses of colorectal motility to noxious stimuli in rats. Colorectal motility was measured in vivo in anaesthetized rats. Administration of a noxious stimulant, capsaicin, into the colorectal lumen enhanced colorectal motility in male rats but not in female rats. Quantitative PCR and immunohistochemistry showed that TRPV1 expression levels in the dorsal root ganglia and in the colorectal mucosa were comparable in male and female rats. When a GABAA receptor inhibitor was intrathecally administered to the L6-S1 level of the spinal cord, colorectal motility was facilitated in response to intracolonic capsaicin even in female rats. The capsaicin-induced response in the presence of the GABA blocker in female rats was inhibited by intrathecal administration of 5-HT2 and -3 receptor antagonists but not by a D2-like dopamine receptor antagonist. Our findings demonstrate that intracolonic noxious stimulation activates GABAergic and serotoninergic descending neurons in female rats, whereas serotoninergic and dopaminergic neurons are dominantly activated in male rats. Thus, the difference in the descending neurons operating after noxious stimulation would be responsible for the sexually dimorphic responses of colorectal motility. Our findings provide a novel insight into pathophysiological mechanisms of sex differences in functional defaecation disorders such as irritable bowel syndrome.

Roles of the noradrenergic nucleus locus coeruleus and dopaminergic nucleus A11 region as supraspinal defecation centers in rats.

We previously demonstrated that administration of norepinephrine, dopamine, and serotonin into the lumbosacral defecation center caused propulsive contractions of the colorectum. It is known that the monoamines in the spinal cord are released mainly from descending neurons in the brainstem. In fact, stimulation of the medullary raphe nuclei, the origin of descending serotonergic neurons, enhances colorectal motility via the lumbosacral defecation center. Therefore, the purpose of this study was to examine the roles of the noradrenergic nucleus locus coeruleus (LC) and dopaminergic nucleus A11 region in the defecation reflex. Colorectal motility was measured with a balloon in anesthetized rats. Electrical stimulation of the LC and A11 region increased colorectal pressure only when a GABAA receptor antagonist was injected into the lumbosacral spinal cord. The effects of the LC stimulation and A11 region stimulation on colorectal motility were inhibited by antagonists of α1-adrenoceptors and D2-like dopamine receptors injected into the lumbosacral spinal cord, respectively. Spinal injection of a norepinephrine-dopamine reuptake inhibitor augmented the colokinetic effect of LC stimulation. The effect of stimulation of each nucleus was abolished by surgical severing of the parasympathetic pelvic nerves. Our findings demonstrate that activation of descending noradrenergic neurons from the LC and descending dopaminergic neurons from the A11 region causes enhancement of colorectal motility via the lumbosacral defecation center. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.NEW & NOTEWORTHY The present study demonstrates that electrical and chemical stimulations of the locus coeruleus or A11 region augment contractions of the colorectum. The effects of locus coeruleus and A11 stimulations on colorectal motility are due to activation of α1-adrenoceptors and D2-like dopamine receptors in the lumbosacral defecation center, respectively. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.

Hypothermia induces changes in the alternative splicing pattern of cold-inducible RNA-binding protein transcripts in a non-hibernator, the mouse.

Cold-inducible RNA-binding protein (CIRBP) plays important roles in protection against harmful effects of cold temperature. We previously found that several splicing variants of CIRBP mRNA are constitutively expressed in the heart of non-hibernating euthermic hamsters and that one of the variants is predominantly expressed with remarkable reduction in the expression of other variants in hibernating hypothermic hamsters. The aim of this study was to determine whether the regulation of alternative splicing is a common function in a non-hibernator, the mouse. The expression of CIRBP mRNA was assessed by RT-PCR. In euthermic control mice, several splicing variants of CIRBP mRNA were detected in various organs. When hypothermia was induced in mice by using isoflurane anesthesia, the short form variant, which encodes full-length functional CIRBP, was predominantly detected. Keeping body temperature of anesthetized mice at 37°C prevented changes in the splicing pattern. Exposure of mice to a low temperature did not change the splicing pattern, suggesting that endogenous neuronal and/or humoral pathways activated in response to cold stimuli applied to the body surface play minor roles. In agreement with this, the shift in alternative splicing was reproduced in isolated leukocytes in vitro when they were incubated at 28°C. Since application of a TRPM8 or TRPA1 agonist at 37°C failed to promote the shift in the splicing pattern, it seems likely that cold-sensitive channels are not involved in the splicing regulation. Therefore, it is probable that a substantial reduction of temperature is a major cause of the regulation of alternative splicing of CIRBP transcripts. The regulatory system of CIRBP expression at the level of alternative splicing, which was originally discovered in the hibernating hamster, commonly exists in non-hibernators such as mice.

ATP-dependent potassium channels contribute to motor regulation of esophageal striated muscle in rats.

The aim of the present study was to clarify roles of ATP-dependent potassium channels (KATP channels) in motility of the striated muscle portion in the esophagus. An isolated segment of the rat esophagus was placed in an organ bath and mechanical responses were recorded using a force transducer. Electrical stimulation of the vagus nerve evoked contractile response of striated muscle in the esophageal segment. Application of glibenclamide, an antagonist of KATP channels, increased amplitude of vagally mediated twitch contractions of the rat esophagus. On the other hand, minoxidil, an agonist of KATP channels, decreased amplitude of twitch contractions. RT-PCR revealed the expression of subunits of KATP channels in esophageal tissue. In addition, immunopositivity for subunits of KATP channels was observed in the striated muscle cells of the esophageal muscle layer. These findings indicate that KATP channels contribute to motor regulation of striated muscle in the rat esophagus.

Mild hypothermia causes a shift in the alternative splicing of cold-inducible RNA-binding protein transcripts in Syrian hamsters.

Cold-shock proteins are thought to participate in the cold-tolerant nature of hibernating animals. We previously demonstrated that an alternative splicing may allow rapid induction of functional cold-inducible RNA-binding protein (CIRBP) in the hamster heart. The purpose of the present study was to determine the major cause of the alternative splicing in Syrian hamsters. RT-PCR analysis revealed that CIRBP mRNA is constitutively expressed in the heart, brain, lung, liver, and kidney of nonhibernating euthermic hamsters with several alternative splicing variants. In contrast, the short variant containing an open-reading frame for functional CIRBP was dominantly found in the hibernating animals. Keeping the animals in a cold and dark environment did not cause a shift in the alternative splicing. Induction of hypothermia by central administration of an adenosine A1-receptor agonist reproduced the shift in the splicing pattern. However, the agonist failed to shift the pattern when body temperature was kept at 37°C, suggesting that central adenosine A1 receptors are not directly linked to the shift of the alternative splicing. Rapid reduction of body temperature to 10°C by isoflurane anesthesia combined with cooling did not alter the splicing pattern, but maintenance of mild hypothermia (~28°C) for 2 h elicited the shift in the pattern. The results suggest that animals need to be maintained at mild hypothermia for an adequate duration to induce the shift in the alternative splicing. This is applicable to natural hibernation because hamsters entering hibernation show a gradual decrease in body temperature, being maintained at mild hypothermia for several hours.

Characterization of peristaltic motility in the striated muscle portion of the esophagus using a novel in vivo method in rats.

BACKGROUND: Esophageal peristalsis is controlled by the brainstem via vago-vagal reflex. However, the precise regulatory mechanisms in the striated muscle portion are largely unknown. The aim of this study was to characterize peristaltic motility in the portion of the esophagus using a novel in vivo method in rats. METHODS: A balloon-tipped catheter was placed in the esophagus of a rat anesthetized with urethane. To induce esophageal peristalsis, the balloon was inflated by water injection. KEY RESULTS: When the balloon was inflated near the bronchial bifurcation, the balloon was transported in the aboral direction. Vagotomy abolished the peristaltic response. The threshold volume for inducing esophageal peristalsis varied according to the velocity of balloon distention; the volume being effective to induce peristalsis at a low inflation speed was smaller than the threshold volume at a rapid inflation speed. Even in the absence of inflation, keeping the balloon inside the esophagus during an interval period prevented subsequent induction of peristaltic motility. In addition, a nitric oxide synthase inhibitor abolished the induction of esophageal peristalsis. CONCLUSIONS AND INFERENCES: Our findings suggest that (a) in addition to the intensity, the velocity of distention is important for activating the mechanosensory mechanism to induce esophageal peristalsis, (b) tonic inputs from afferent fibers located at the mucosa may reduce the excitability of mechanosensors which is necessary for inducing peristalsis, and (c) nitric oxide plays essential roles in the induction of esophageal peristalsis. These results provide novel insights into the regulatory mechanisms of esophageal motility.

The Mechanism Enabling Hibernation in Mammals.

Some rodents including squirrels and hamsters undergo hibernation. During hibernation, body temperature drops to only a few degrees above ambient temperature. The suppression of whole-body energy expenditure is associated with regulated, but not passive, reduction of cellular metabolism. The heart retains the ability to beat constantly, although body temperature drops to less than 10 °C during hibernation. Cardiac myocytes of hibernating mammals are characterized by reduced Ca2+ entry into the cell membrane and a concomitant enhancement of Ca2+ release from and reuptake by the sarcoplasmic reticulum. These adaptive changes would help in preventing excessive Ca2+ entry and its overload and in maintaining the resting levels of intracellular Ca2+. Adaptive changes in gene expression in the heart prior to hibernation may be indispensable for acquiring cold resistance. In addition, protective effects of cold-shock proteins are thought to have an important role. We recently reported the unique expression pattern of cold-inducible RNA-binding protein (CIRP) in the hearts of hibernating hamsters. The CIRP mRNA is constitutively expressed in the heart of a nonhibernating euthermic hamster with several different forms probably due to alternative splicing. The short product contained the complete open reading frame for full-length CIRP, while the long product had inserted sequences containing a stop codon, suggesting production of a C-terminal deletion isoform of CIRP. In contrast to nonhibernating hamsters, only the short product was found in hibernating animals. Thus, these results indicate that CIRP expression in the hamster heart is regulated at the level of alternative splicing, which would permit a rapid increment of functional CIRP when entering hibernation. We will summarize the current understanding of the cold-resistant property of the heart in hibernating animals.

Descending monoaminergic pathways projecting to the spinal defecation center enhance colorectal motility in rats.

The central regulating mechanisms of defecation, especially roles of the spinal defecation center, are still unclear. We have shown that monoamines including norepinephrine, dopamine, and serotonin injected into the spinal defecation center cause propulsive contractions of the colorectum. These monoamines are the main neurotransmitters of descending pain inhibitory pathways. Therefore, we hypothesized that noxious stimuli in the colorectum would activate the descending monoaminergic pathways projecting to the spinal defecation center and that subsequently released endogenous monoamine neurotransmitters would enhance colorectal motility. Colorectal motility was measured in rats anesthetized with α-chloralose and ketamine. As a noxious stimulus, capsaicin was administered into the colorectal lumen. To interrupt neuronal transmission in the spinal defecation center, antagonists of norepinephrine, dopamine, and/or serotonin receptors were injected intrathecally at the L6-S1 spinal level, where the spinal defecation center is located. Intraluminal administration of capsaicin, acting on the transient receptor potential vanilloid 1 channel, caused transient propulsive contractions. The effect of capsaicin was abolished by surgical severing of the pelvic nerves or thoracic spinal transection at the T4 level. Capsaicin-induced contractions were blocked by preinjection of D2-like dopamine receptor and 5-hydroxytryptamine subtype 2 and 3 receptor antagonists into the spinal defecation center. We demonstrated that intraluminally administered capsaicin causes propulsive colorectal motility through reflex pathways involving the spinal and supraspinal defecation centers. Our results provide evidence that descending monoaminergic neurons are activated by noxious stimulation to the colorectum, leading to facilitation of colorectal motility. NEW & NOTEWORTHY The present study demonstrates that noxious stimuli in the colorectum activates the descending monoaminergic pathways projecting to the spinal defecation center and that subsequently released endogenous monoamine neurotransmitters, serotonin and dopamine, enhance colorectal motility. Our findings provide a possible explanation of the concurrent appearance of abdominal pain and bowel disorder in irritable bowel syndrome patients. Thus the present study may provide new insights into understanding of mechanisms of colorectal dysfunction involving the central nervous system.

Local regulatory mechanism to coordinate colorectal motility in rats.

The presence of a fecal pellet in the colorectum causes ascending contraction and descending relaxation, propelling the pellet aborally. However, random occurrence of the reflexes at multiple sites would disturb sequential excretion of the pellets, resulting in inefficient defecation. Hence, we postulated that a regulatory mechanism to coordinate peristaltic motility initiated at adjacent portions of the colorectum may exist. Colorectal motility was recorded with balloons located at 2 cm, 5 cm and 7 cm from the anus in vivo in anesthetized rats. The presence of a balloon in the colorectum inhibited motility of the oral side and enhanced motility of the anal side. Both the ascending inhibitory and descending facilitatory actions were unaffected by cutting the pelvic nerves, suggesting little contribution of the lumbosacral defecation center. In contrast, disrupting the continuity of the enteric nervous system abolished the local reflex mechanism. The ascending inhibitory pathway operated in a condition in which facilitatory input from the lumbosacral defecation center was fully activated by intrathecal injection of ghrelin. We also found that functional impairment of the local reflex pathways was evident in rats that recovered from 2,4,6-trinitrobenzensulfonic acid-induced colitis. These results demonstrate that an intrinsic regulatory mechanism to coordinate peristaltic motility initiated at adjacent portions exists in the rat colorectum. The regulation may be beneficial to propel multiple pellets efficiently. In addition, impairment of the local regulatory mechanism might be involved in postinflammatory dysmotility in the colorectum.

Medullary raphe nuclei activate the lumbosacral defecation center through the descending serotonergic pathway to regulate colorectal motility in rats.

Colorectal motility is regulated by two defecation centers located in the brain and spinal cord. In previous studies, we have shown that administration of serotonin (5-HT) in the lumbosacral spinal cord causes enhancement of colorectal motility. Because spinal 5-HT is derived from neurons of the medullary raphe nuclei, including the raphe magnus, raphe obscurus, and raphe pallidus, we examined whether stimulation of the medullary raphe nuclei enhances colorectal motility via the lumbosacral defecation center. Colorectal pressure was recorded with a balloon in vivo in anesthetized rats. Electrical stimulation of the medullary raphe nuclei failed to enhance colorectal motility. Because GABAergic neurons can be simultaneously activated by the raphe stimulation and released GABA masks accelerating actions of the raphe nuclei on the lumbosacral defecation center, a GABAA receptor antagonist was preinjected intrathecally to manifest excitatory responses. When spinal GABAA receptors were blocked by the antagonist, electrical stimulation of the medullary raphe nuclei increased colorectal contractions. This effect of the raphe nuclei was inhibited by intrathecal injection of 5-hydroxytryptamine type 2 (5-HT2) and type 3 (5-HT3) receptor antagonists. In addition, injection of a selective 5-HT reuptake inhibitor in the lumbosacral spinal cord augmented the raphe stimulation-induced enhancement of colorectal motility. Transection of the pelvic nerves, but not transection of the colonic nerves, prevented the effect of the raphe nuclei on colorectal motility. These results demonstrate that activation of the medullary raphe nuclei causes augmented contractions of the colorectum via 5-HT2 and 5-HT3 receptors in the lumbosacral defecation center. NEW & NOTEWORTHY We have shown that electrical stimulation of the medullary raphe nuclei causes augmented contractions of the colorectum via pelvic nerves in rats. The effect of the medullary raphe nuclei on colorectal motility is exerted through activation of 5-hydroxytryptamine type 2 and type 3 receptors in the lumbosacral defecation center. The descending serotoninergic raphespinal tract represents new potential therapeutic targets against colorectal dysmotility such as irritable bowel syndrome.

Rapid regulation of sialidase activity in response to neural activity and sialic acid removal during memory processing in rat hippocampus.

Sialidase cleaves sialic acids on the extracellular cell surface as well as inside the cell and is necessary for normal long-term potentiation (LTP) at mossy fiber-CA3 pyramidal cell synapses and for hippocampus-dependent spatial memory. Here, we investigated in detail the role of sialidase in memory processing. Sialidase activity measured with 4-methylumbelliferyl-α-d-N-acetylneuraminic acid (4MU-Neu5Ac) or 5-bromo-4-chloroindol-3-yl-α-d-N-acetylneuraminic acid (X-Neu5Ac) and Fast Red Violet LB was increased by high-K+-induced membrane depolarization. Sialidase activity was also increased by chemical LTP induction with forskolin and activation of BDNF signaling, non-NMDA receptors, or NMDA receptors. The increase in sialidase activity with neural excitation appears to be caused not by secreted sialidase or by an increase in sialidase expression but by a change in the subcellular localization of sialidase. Astrocytes as well as neurons are also involved in the neural activity-dependent increase in sialidase activity. Sialidase activity visualized with a benzothiazolylphenol-based sialic acid derivative (BTP3-Neu5Ac), a highly sensitive histochemical imaging probe for sialidase activity, at the CA3 stratum lucidum of rat acute hippocampal slices was immediately increased in response to LTP-inducible high-frequency stimulation on a time scale of seconds. To obtain direct evidence for sialic acid removal on the extracellular cell surface during neural excitation, the extracellular free sialic acid level in the hippocampus was monitored using in vivo microdialysis. The free sialic acid level was increased by high-K+-induced membrane depolarization. Desialylation also occurred during hippocampus-dependent memory formation in a contextual fear-conditioning paradigm. Our results show that neural activity-dependent desialylation by sialidase may be involved in hippocampal memory processing.

Visualization of sialidase activity in Mammalian tissues and cancer detection with a novel fluorescent sialidase substrate.

Sialidase removes sialic acid from sialoglycoconjugates and plays crucial roles in many physiological and pathological processes. Various human cancers express an abnormally high level of the plasma membrane-associated sialidase isoform.Visualization of sialidase activity in living mammalian tissues would be useful not only for understanding sialidase functions but also for cancer diagnosis. However, since enzyme activity of mammalian sialidase is remarkably weak compared with that of bacterial and viral sialidases, it has been difficult to detect sialidase activity in mammalian tissues. We synthesized a novel benzothiazolylphenol-based sialic acid derivative (BTP-Neu5Ac) as a fluorescent sialidase substrate. BTP-Neu5Ac can visualize sialidase activities sensitively and selectively in acute rat brain slices. Cancer cells implanted orthotopically in mouse colons and human colon cancers (stages T3-T4) were also clearly detected with BTP-Neu5Ac. The results suggest that BTP-Neu5Ac is useful for histochemical imaging of sialidase activities.

Improvement of depression-like behavior and memory impairment with the ethanol extract of Pleurotus eryngii in ovariectomized rats.

Ethanol extract of Pleurotus eryngii (DC.) QUÉL has estrogen-like activities that protect against bone loss caused by estrogen deficiency. In the present study, we investigated the effect of P. eryngii on depression-like behavior and memory impairment in ovariectomized (OVX) rats. Immobility time during a forced swimming test was significantly longer for OVX rats than for sham-operated rats. The depression-like behavior in OVX rats was improved by long-term administration of the ethanol extract of P. eryngii (500 mg/kg body weight (b.w.)/d). Spatial memory impairment in OVX rats assessed by the Morris water maze test was also improved by P. eryngii extract without any effect on motility. These results suggested that P. eryngii extract has estrogen-like improvement activity against depression-like behavior and memory impairment in OVX rats. Additionally, increase in the amount of synaptosomal zinc after ovariectomy was inhibited by P. eryngii extract. Since zinc in synaptic vesicles is important for memory function and is linked to the pathophysiology of depression, normalization of zinc signaling would be involved in the beneficial effect of P. eryngii extract on neurological disorders after ovariectomy.