Imeglimin prevents visceral hypersensitivity and colonic hyperpermeability in irritable bowel syndrome rat model.

Visceral hypersensitivity and leaky gut, which are mediated via corticotropin-releasing factor (CRF) and Toll-like receptor 4 are key pathophysiology of irritable bowel syndrome (IBS). Metformin was reported to improve these gastrointestinal (GI) changes. In this study, we attempted to determine the effects of imeglimin, which was synthesized from metformin on GI function in IBS rat models. Imeglimin blocked lipopolysaccharide- or CRF-induced visceral hypersensitivity and colonic hyperpermeability. These effects were prevented by compound C or naloxone. These results suggest that imeglimin may be effective for the treatment of IBS by improved visceral sensation and colonic barrier via AMPK and opioid receptor.

Discussion of Research Priorities for Gait Disorders in Parkinson's Disease.

Gait and balance abnormalities develop commonly in Parkinson's disease and are among the motor symptoms most disabling and refractory to dopaminergic or other treatments, including deep brain stimulation. Efforts to develop effective therapies are challenged by limited understanding of these complex disorders. There is a major need for novel and appropriately targeted research to expedite progress in this area. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society has charged a panel of experts in the field to consider the current knowledge gaps and determine the research routes with highest potential to generate groundbreaking data. © 2021 International Parkinson and Movement Disorder Society.

Knee dynamics during take-off and landing in spike jumps performed by volleyball players with patellar tendinopathy.

[Purpose] Patellar tendinopathy is a common sports injury. The risk factors for this injury can be categorized as intrinsic, extrinsic, and dynamic. We examined the dynamic factors in this study. [Participants and Methods] The participants were volleyball players who were assigned to a patient group (n=6) if they had medial patellar tendinopathy in the left knee or to a control group (n=7) otherwise. The participants performed spike jumps, and their ground reaction force and three-dimensional kinematic data were recorded. Knee angle and moment data were extracted at the peak extension moment of take-off and landing. [Results] The two groups showed no differences in knee angles. A tendency for abduction/external rotation moments at take-off and landing on both sides was observed in the control group, while the patient group showed adduction and internal rotation moments at take-off and adduction moment at landing in the left (injured) knee. [Conclusion] The observed knee joint moments in the left (injured) knee of the patient group may have been involved in the pathophysiological mechanism underlying the development of patellar tendinopathy.

EMA401, an angiotensin II type 2 receptor antagonist blocks visceral hypersensitivity and colonic hyperpermeability in rat model of irritable bowel syndrome.

Visceral hypersensitivity and impaired gut barrier are crucial pathophysiology of irritable bowel syndrome (IBS), and injection of lipopolysaccharide or corticotropin-releasing factor, and repeated water avoidance stress simulate these gastrointestinal changes in rat (IBS models). We previously demonstrated that losartan, an angiotensin II type 1 (AT1) receptor antagonist prevented these changes, and we attempted to determine the effects of EMA401, an AT2 receptor antagonist in the current study. EMA401 blocked visceral hypersensitivity and colonic hyperpermeability in these models, and naloxone reversed the effects by EMA401. These results suggest that EMA401 may improve gut function via opioid signaling in IBS.

The Responsiveness of Triaxial Accelerometer Measurement of Gait Ataxia Is Higher than That of the Scale for the Assessment and Rating of Ataxia in the Early Stages of Spinocerebellar Degeneration.

We reported previously that the average medial-lateral gait amplitude while walking on a straight path determined using triaxial accelerometers fixed on the middle of the upper back may be a quantitative and concise indicator for the severity of cerebellar ataxia. Considering that gait ataxia is a typical initial symptom in a variety of spinocerebellar degeneration (SCD), we aimed to develop quantitative biomarkers for cerebellar ataxia as metric variables. We used triaxial accelerometers to analyze gait parameters in 14 patients with SCD at 3 points over 3 years (at baseline, 1.5 years and 3 years). Analysis of covariance (ANCOVA) models adjusted for the baseline scores were used to estimate sample sizes. The mean medial-lateral amplitude (ML) gained by a triaxial accelerometer fixed on upper back could detect the each 1.5-year change. In the 14 patients, the mean ML(m) was 0.032 ± 0.007(SD) at entry, 0.037 ± 0.008 after 1.5-year follow, and 0.042 ± 0.020 after 3-year follow. In contrast, SARA gait scores were 2.9, 2.9, and 3.0, respectively. The responsiveness of the quantitative evaluation of gait ataxia by triaxial accelerometers is higher than that of the SARA within a 1.5-year follow-up period. Gait analysis by triaxial accelerometers will be complementary to the evaluation of scales like SARA in the assessment of clinical severity of SCD patients in early stage.

Pioglitazone improves visceral sensation and colonic permeability in a rat model of irritable bowel syndrome.

Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-γ activation by pioglitazone may be useful for IBS treatment.

Metformin inhibits visceral allodynia and increased gut permeability induced by stress in rats.

BACKGROUND AND AIM: Metformin has been shown to have anti-cytokine property. Lipopolysaccharide (LPS)-induced or repeated water avoidance stress (WAS)-induced visceral allodynia and increased gut permeability were pro-inflammatory cytokine-dependent responses, which were considered to be animal models of irritable bowel syndrome (IBS). We hypothesized that metformin improves symptoms in the patients with IBS by attenuating these visceral changes and tested the hypothesis in rats. METHODS: The threshold of the visceromotor response induced by colonic balloon distention was measured. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue for 15 min spectrophotometrically. RESULTS: Subcutaneously injected LPS (1 mg/kg) reduced the threshold of visceromotor response, and metformin (5-50 mg/kg for 3 days) intraperitoneally attenuated this response in a dose-dependent manner. Repeated WAS (1 h daily for 3 days) induced visceral allodynia, which was also blocked by metformin. The antinociceptive effect of metformin on the LPS-induced allodynia was reversed by compound C, an adenosine monophosphate-activated protein kinase inhibitor or NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor but not modified by naloxone. Additionally, it was blocked by sulpiride, a dopamine D2 receptor antagonist, but domperidone, a peripheral dopamine D2 receptor antagonist, did not alter it. Metformin also blocked the LPS-induced or repeated WAS-induced increased colonic permeability. CONCLUSIONS: Metformin attenuated the visceral allodynia and increased gut permeability in animal IBS models. These actions may be evoked via activation of adenosine monophosphate-activated protein kinase, nitric oxide, and central dopamine D2 pathways. These results indicate the possibility that metformin can be useful for treating IBS.

Glucagon-like peptide-1 analog, liraglutide, improves visceral sensation and gut permeability in rats.

BACKGROUND AND AIM: A glucagon-like peptide-1 analog, liraglutide, has been reported to block inflammatory somatic pain. We hypothesized that liraglutide attenuates lipopolysaccharide (LPS)-induced and repeated water avoidance stress (WAS)-induced visceral hypersensitivity and tested the hypothesis in rats. METHODS: The threshold of the visceromotor response induced by colonic balloon distention was measured to assess visceral sensation. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue spectrophotometrically, which was instilled in the proximal colon for 15 min. The interleukin-6 level in colonic mucosa was also quantified using ELISA. RESULTS: Subcutaneously injected LPS (1 mg/kg) reduced the visceromotor response threshold after 3 h. Liraglutide (300 µg/kg subcutaneously) at 15 h and 30 min before injecting LPS eliminated LPS-induced allodynia. It also blocked the allodynia induced by repeated water avoidance stress for 1 h for three consecutive days. Neither vagotomy nor naloxone altered the antinociceptive effect of liraglutide, but NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, blocked it. LPS increased colonic permeability and the interleukin-6 level, and the analog significantly inhibited these responses. CONCLUSIONS: This study suggests that liraglutide blocked LPS-induced visceral allodynia, which may be a nitric oxide-dependent response, and was probably mediated by inhibiting pro-inflammatory cytokine production and attenuating the increased gut permeability. Because the LPS-cytokine system is considered to contribute to altered visceral sensation in irritable bowel syndrome, these results indicate the possibility that liraglutide can be useful for treating this disease.

Physiology of freezing of gait.

Freezing of gait (FOG) is a common and debilitating, but largely mysterious, symptom of Parkinson disease. In this review, we will discuss the cerebral substrate of FOG focusing on brain physiology and animal models. Walking is a combination of automatic movement processes, afferent information processing, and intentional adjustments. Thus, normal gait requires a delicate balance between various interacting neuronal systems. To further understand gait control and specifically FOG, we will discuss the basic physiology of gait, animal models of gait disturbance including FOG, alternative etiologies of FOG, and functional magnetic resonance studies investigating FOG. The outcomes of these studies point to a dynamic network of cortical areas such as the supplementary motor area, as well as subcortical areas such as the striatum and the mesencephalic locomotor region including the pedunculopontine nucleus (PPN). Additionally, we will review PPN (area) stimulation as a possible treatment for FOG, and ponder whether PPN stimulation truly is the right step forward. Ann Neurol 2016;80:644-659.

Repeated water avoidance stress induces visceral hypersensitivity: Role of interleukin-1, interleukin-6, and peripheral corticotropin-releasing factor.

BACKGROUND AND AIM: Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin-releasing factor (CRF), mast cells, and pro-inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue. METHODS: Abdominal muscle contractions induced by colonic balloon distention, that is, visceromotor response (VMR) was detected electrophysiologically in conscious rats. WAS or sham stress as control for 1 h daily was loaded, and the threshold of VMR was determined before and at 24 h after the stress. RESULTS: Repeated WAS for three consecutive days reduced the threshold of VMR, but sham stress did not induce any change. Astressin, a CRF receptor antagonist (50 µg/kg) intraperitoneally (ip) at 10 min before each WAS session, prevented the visceral allodynia, but the antagonist (200 µg/kg) ip at 30 min and 15 h before measurement of the threshold after completing 3-day stress session did not modify the response. Ketotifen, a mast cell stabilizer (3 mg/kg), anakinra, an interleukin (IL)-1 receptor antagonist (20 mg/kg) or IL-6 antibody (16.6 µg/kg) ip for two times before the measurement abolished the response. CONCLUSIONS: Repeated WAS for three consecutive days induced visceral allodynia, which was mediated through mast cells, IL-1, and IL-6 pathways. Inhibition of peripheral CRF signaling prevented but did not reverse this response, suggesting that peripheral CRF may be an essential trigger but may not contribute to the maintenance of repeated WAS-induced visceral allodynia.

Brainstem control of locomotion and muscle tone with special reference to the role of the mesopontine tegmentum and medullary reticulospinal systems.

The lateral part of the mesopontine tegmentum contains functionally important structures involved in the control of posture and gait. Specifically, the mesencephalic locomotor region, which may consist of the cuneiform nucleus and pedunculopontine tegmental nucleus (PPN), occupies the interest with respect to the pathophysiology of posture-gait disorders. The purpose of this article is to review the mechanisms involved in the control of postural muscle tone and locomotion by the mesopontine tegmentum and the pontomedullary reticulospinal system. To make interpretation and discussion more robust, the above issue is considered largely based on our findings in the experiments using decerebrate cat preparations in addition to the results in animal experimentations and clinical investigations in other laboratories. Our investigations revealed the presence of functional topographical organizations with respect to the regulation of postural muscle tone and locomotion in both the mesopontine tegmentum and the pontomedullary reticulospinal system. These organizations were modified by neurotransmitter systems, particularly the cholinergic PPN projection to the pontine reticular formation. Because efferents from the forebrain structures as well as the cerebellum converge to the mesencephalic and pontomedullary reticular formation, changes in these organizations may be involved in the appropriate regulation of posture-gait synergy depending on the behavioral context. On the other hand, abnormal signals from the higher motor centers may produce dysfunction of the mesencephalic-reticulospinal system. Here we highlight the significance of elucidating the mechanisms of the mesencephalic-reticulospinal control of posture and locomotion so that thorough understanding of the pathophysiological mechanisms of posture-gait disorders can be made.

Levodopa acts centrally to induce an antinociceptive action against colonic distension through activation of D2 dopamine receptors and the orexinergic system in the brain in conscious rats.

Levodopa possesses antinociceptive actions against several somatic pain conditions. However, we do not know at this moment whether levodopa is also effective to visceral pain. The present study was therefore performed to clarify whether levodopa is effective to visceral pain and its mechanisms. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously (80 mg/rat) or intracisternally (2.5 µg/rat) administered levodopa significantly increased the threshold of colonic distension-induced AWR in conscious rats. The dose difference to induce the antinociceptive action suggests levodopa acts centrally to exert its antinociceptive action against colonic distension. While neither sulpiride, a D2 dopamine receptor antagonist, nor SCH23390, a D1 dopamine receptor antagonist by itself changed the threshold of colonic distension-induced AWR, the intracisternally injected levodopa-induced antinociceptive action was significantly blocked by pretreatment with subcutaneously administered sulpiride but not SCH23390. Treatment with intracisternal SB334867, an orexin 1 receptor antagonist, significantly blocked the subcutaneously administered levodopa-induced antinociceptive action. These results suggest that levodopa acts centrally to induce an antinociceptive action against colonic distension through activation of D2 dopamine receptors and the orexinergic system in the brain.

Co-localization of TRPV2 and insulin-like growth factor-I receptor in olfactory neurons in adult and fetal mouse.

TRPV2, a member of the transient receptor potential family, has been isolated as a capsaicin-receptor homolog and is thought to respond to noxious heat. Here we show that TRPV2 mRNA is predominantly expressed in the subpopulation of olfactory sensory neurons (OSNs). We carried out histochemical analyses of TRPV2 and insulin-like growth factor-I receptor (IGF-IR) using in situ hybridization and immunofluorescence in the adult olfactory system. In olfactory mucosa, intensive TRPV2 immunostaining was observed at the olfactory axon bundles but not at the soma. TRPV2-positive labeling was preferentially found in the olfactory nerve layer in the olfactory bulb (OB). Furthermore, we demonstrated that a positive signal for IGF-IR mRNA was detected in OSNs expressing TRPV2 mRNA. In embryonic stages, TRPV2 immunoreactivity was observed on axon bundles of developing OSNs in the nasal region starting from 12.5 d of gestation and through fetal development. Observations in this study suggest that TRPV2 coupled with IGF-IR localizes to growing olfactory axons in the OSNs.

Tranilast alleviates visceral hypersensitivity and colonic hyperpermeability by suppressing NLRP3 inflammasome activation in irritable bowel syndrome rat models.

Visceral hypersensitivity resulting from compromised gut barrier with activated immune system is a key feature of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and Toll-like receptor 4 (TLR4) activate proinflammatory cytokine signaling to induce these changes, which is one of the mechanisms of IBS. As activation of the NLRP3 inflammasome by lipopolysaccharide (LPS) or TLR4 leads to release interleukin (IL)-1ß, the NLRP3 inflammasome may be involved in the pathophysiology of IBS. Tranilast, an anti-allergic drug has been demonstrated to inhibit the NLRP3 inflammasome, and we evaluated the impact of tranilast on visceral hypersensitivity and colonic hyperpermeability induced by LPS or CRF (IBS rat model). Visceral pain threshold caused by colonic balloon distention was measured by monitoring abdominal muscle contractions electrophysiologically. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue. Colonic protein levels of NLRP3 and IL-1ß were assessed by immunoblot or ELISA. Intragastric administration of tranilast (20-200 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Simultaneously, tranilast also abolished these alterations induced by CRF (50 µg/kg). LPS increased colonic protein levels of NLRP3 and IL-1ß, and tranilast inhibited these changes. ß-hydroxy butyrate, an NLRP3 inhibitor, also abolished visceral hypersensitivity and colonic hyperpermeability caused by LPS. In contrast, IL-1ß induced similar GI alterations to LPS, which were not modified by tranilast. In conclusion, tranilast improved visceral pain and colonic barrier by suppression of the NLRP3 inflammasome in IBS rat models. Tranilast may be useful for IBS treating.

Evolutionary origin of alpha rhythms in vertebrates.

The purpose of this review extends beyond the traditional triune brain model, aiming to elucidate the evolutionary aspects of alpha rhythms in vertebrates. The forebrain, comprising the telencephalon (pallium) and diencephalon (thalamus, hypothalamus), is a common feature in the brains of all vertebrates. In mammals, evolution has prioritized the development of the forebrain, especially the neocortex, over the midbrain (mesencephalon) optic tectum, which serves as the prototype for the visual brain. This evolution enables mammals to process visual information in the retina-thalamus (lateral geniculate nucleus)-occipital cortex pathway. The origin of posterior-dominant alpha rhythms observed in mammals in quiet and dark environments is not solely attributed to cholinergic pontine nuclei cells functioning as a 10 Hz pacemaker in the brainstem. It also involves the ability of the neocortex's cortical layers to generate traveling waves of alpha rhythms with waxing and waning characteristics. The utilization of alpha rhythms might have facilitated the shift of attention from external visual inputs to internal cognitive processes as an adaptation to thrive in dark environments. The evolution of alpha rhythms might trace back to the dinosaur era, suggesting that enhanced cortical connectivity linked to alpha bands could have facilitated the development of nocturnal awakening in the ancestors of mammals. In fishes, reptiles, and birds, the pallium lacks a cortical layer. However, there is a lack of research clearly observing dominant alpha rhythms in the pallium or organized nuclear structures in fishes, reptiles, or birds. Through convergent evolution, the pallium of birds, which exhibits cortex-like fiber architecture, has not only acquired advanced cognitive and motor abilities but also the capability to generate low-frequency oscillations (4-25 Hz) resembling alpha rhythms. This suggests that the origins of alpha rhythms might lie in the pallium of a common ancestor of birds and mammals.

Neurophysiology of gait: from the spinal cord to the frontal lobe.

Locomotion is a purposeful, goal-directed behavior initiated by signals arising from either volitional processing in the cerebral cortex or emotional processing in the limbic system. Regardless of whether the locomotion initiation is volitional or emotional, locomotion is accompanied by automatic controlled movement processes, such as the adjustment of postural muscle tone and rhythmic limb movements. Sensori-motor integration in the brainstem and the spinal cord plays crucial roles in this process. The basic locomotor motor pattern is generated by spinal interneuronal networks, termed central pattern generators (CPGs). Responding to signals in proprioceptive and skin afferents, the spinal interneuronal networks modify the locomotor pattern in cooperation with descending signals from the brainstem structures and the cerebral cortex. Information processing between the basal ganglia, the cerebellum, and the brainstem may enable automatic regulation of muscle tone and rhythmic limb movements in the absence of conscious awareness. However, when a locomoting subject encounters obstacles, the subject has to intentionally adjust bodily alignment to guide limb movements. Such an intentional gait modification requires motor programming in the premotor cortices. The motor programs utilize one's bodily information, such as the body schema, which is preserved and updated in the temporoparietal cortex. The motor programs are transmitted to the brainstem by the corticoreticulospinal system, so that one's posture is anticipatorily controlled. These processes enable the corticospinal system to generate limb trajectory and achieve accurate foot placement. Loops from the motor cortical areas to the basal ganglia and the cerebellum can serve this purpose.

Gait control by the frontal lobe.

The frontal lobe is crucial and contributes to controlling truncal motion, postural responses, and maintaining equilibrium and locomotion. The rich repertoire of frontal gait disorders gives some indication of this complexity. For human walking, it is necessary to simultaneously achieve at least two tasks, such as maintaining a bipedal upright posture and locomotion. Particularly, postural control plays an extremely significant role in enabling the subject to maintain stable gait behaviors to adapt to the environment. To achieve these requirements, the frontal cortex (1) uses cognitive information from the parietal, temporal, and occipital cortices, (2) creates plans and programs of gait behaviors, and (3) acts on the brainstem and spinal cord, where the core posture-gait mechanisms exist. Moreover, the frontal cortex enables one to achieve a variety of gait patterns in response to environmental changes by switching gait patterns from automatic routine to intentionally controlled and learning the new paradigms of gait strategy via networks with the basal ganglia, cerebellum, and limbic structures. This chapter discusses the role of each area of the frontal cortex in behavioral control and attempts to explain how frontal lobe controls walking with special reference to postural control.

Phlorizin attenuates postoperative gastric ileus in rats.

BACKGROUND: Postoperative ileus (POI) is a major complication of abdominal surgery (AS). Impaired gut barrier mediated via Toll-like receptor 4 (TLR4) and interleukin-1 (IL-1) receptor is involved in the development of POI. Phlorizin is a nonselective inhibitor of sodium-linked glucose transporters (SGLTs) and is known to improve lipopolysaccharide (LPS)-induced impaired gut barrier. This study aimed to clarify our hypothesis that AS-induced gastric ileus is mediated via TLR4 and IL-1 signaling, and phlorizin improves the ileus. METHODS: AS consisted of a celiotomy and manipulation of the cecum for 1 min. Gastric emptying (GE) in 20 min with liquid meal was determined 3 h after the surgery in rats. The effect of subcutaneous (s.c.) injection of LPS (1 mg kg-1 ) was also determined 3 h postinjection. KEY RESULTS: AS delayed GE, which was blocked by TAK-242, an inhibitor of TLR4 signaling and anakinra, an IL-1 receptor antagonist. LPS delayed GE, which was also mediated via TLR4 and IL-1 receptor. Phlorizin (80 mg kg-1 , s.c.) significantly improved delayed GE induced by both AS and LPS. However, intragastrical (i.g.) administration of phlorizin did not alter it. As gut mainly expresses SGLT1, SGLT2 may not be inhibited by i.g. phlorizin. The effect of phlorizin was blocked by ghrelin receptor antagonist in the LPS model. CONCLUSIONS & INFERENCES: AS-induced gastric ileus is mediated via TLR4 and IL-1 signaling, which is simulated by LPS. Phlorizin improves the gastric ileus via activation of ghrelin signaling, possibly by inhibition of SGLT2. Phlorizin may be useful for the treatment of POI.

Analysis of the Relationship Between Muscle Tones and Abnormal Postures in a Computational Model.

Patients with Parkinson's disease (PD), a neurodegenerative disorder, exhibit a characteristic posture known as a forward flexed posture. Increased muscle tone is suggested as a possible cause of this abnormal posture. For further analysis, it is necessary to measure muscle tone, but the experimental measurement of muscle tone during standing is challenging. The aim of this study was to examine the hypothesis that "In patients with PD, abnormal postures are those with a small sway at increased muscle tones" using a computational model. The muscle tones of various magnitudes were estimated using the computational model and standing data of patients with PD. The postures with small sway at the estimated muscle tones were then calculated through an optimization method. The postures and sway calculated using the computational model were compared to those of patients with PD. The results showed that the differences in posture and sway between the simulation and experimental results were small at higher muscle tones compared to those considered plausible in healthy subjects by the simulations. This simulation result indicates that the reproduced sway at high muscle tones is similar to that of actual patients with PD and that the reproduced postures with small sway locally at high muscle tones in the simulations are similar to those of patients with PD. The result is consistent with the hypothesis, reinforcing the hypothesis.Clinical relevance- This study implies that improving the increased muscle tone in patients with PD may lead to an improved abnormal posture.