Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Sci Adv ; 9(29): eadh0102, 2023 07 21.
Article in English | MEDLINE | ID: mdl-37478173

ABSTRACT

Vascular cognitive impairment (VCI) refers to cognitive alterations caused by vascular disease, which is associated with various types of dementia. Because chronic cerebral hypoperfusion (CCH) induces VCI, we used bilateral common carotid artery stenosis (BCAS) mice as a CCH-induced VCI model. Transient receptor potential ankyrin 1 (TRPA1), the most redox-sensitive TRP channel, is functionally expressed in the brain. Here, we investigated the pathophysiological role of TRPA1 in CCH-induced VCI. During early-stage CCH, cognitive impairment and white matter injury were induced by BCAS in TRPA1-knockout but not wild-type mice. TRPA1 stimulation with cinnamaldehyde ameliorated BCAS-induced outcomes. RNA sequencing analysis revealed that BCAS increased leukemia inhibitory factor (LIF) in astrocytes. Moreover, hydrogen peroxide-treated TRPA1-stimulated primary astrocyte cultures expressed LIF, and culture medium derived from these cells promoted oligodendrocyte precursor cell myelination. Overall, TRPA1 in astrocytes prevents CCH-induced VCI through LIF production. Therefore, TRPA1 stimulation may be a promising therapeutic approach for VCI.


Subject(s)
Brain Ischemia , Cognitive Dysfunction , Transient Receptor Potential Channels , White Matter , Mice , Animals , Astrocytes , TRPA1 Cation Channel/genetics , Leukemia Inhibitory Factor/pharmacology , Cognitive Dysfunction/complications , Brain Ischemia/complications , Disease Models, Animal , Mice, Inbred C57BL
2.
Int J Mol Sci ; 24(4)2023 Feb 09.
Article in English | MEDLINE | ID: mdl-36834875

ABSTRACT

Abnormalities in the peripheral immune system are involved in the pathophysiology of fibromyalgia, although their contribution to the painful symptoms remains unknown. Our previous study reported the ability of splenocytes to develop pain-like behavior and an association between the central nervous system (CNS) and splenocytes. Since the spleen is directly innervated by sympathetic nerves, this study aimed to examine whether adrenergic receptors are necessary for pain development or maintenance using an acid saline-induced generalized pain (AcGP) model (an experimental model of fibromyalgia) and whether the activation of these receptors is also essential for pain reproduction by the adoptive transfer of AcGP splenocytes. The administration of selective ß2-blockers, including one with only peripheral action, prevented the development but did not reverse the maintenance of pain-like behavior in acid saline-treated C57BL/6J mice. Neither a selective α1-blocker nor an anticholinergic drug affects the development of pain-like behavior. Furthermore, ß2-blockade in donor AcGP mice eliminated pain reproduction in recipient mice injected with AcGP splenocytes. These results suggest that peripheral ß2-adrenergic receptors play an important role in the efferent pathway from the CNS to splenocytes in pain development.


Subject(s)
Fibromyalgia , Receptors, Adrenergic, beta-2 , Mice , Animals , Receptors, Adrenergic, beta-2/metabolism , Fibromyalgia/metabolism , Spleen/metabolism , Mice, Inbred C57BL , Receptors, Adrenergic/metabolism , Pain/metabolism , Central Nervous System/metabolism , Sympathetic Nervous System/metabolism , Receptors, Adrenergic, beta/metabolism , Adrenergic beta-Antagonists/pharmacology
3.
Biol Pharm Bull ; 45(8): 1124-1132, 2022.
Article in English | MEDLINE | ID: mdl-35908894

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms, including impairments in social behavior and repetitive interests. Recent studies have revealed that individuals with ASD also display decreased empathy, ultimately leading to difficulties in social relationships; however, another report indicated that individuals with ASD have enhanced emotional empathy. Nonetheless, the neurobiological mechanisms underlying altered empathy in individuals with ASD remain unclear. In this study, we assessed empathy-like behaviors in valproic acid (VPA)-treated mice-a mouse model of ASD with observational fear learning. We then investigated the brain regions and signaling systems responsible for the altered empathy-like behaviors in VPA-treated mice. As a result, mice prenatally exposed to VPA displayed increased empathy-like behaviors, which were not attributed to altered sensitivity to auditory stimuli or enhanced memory for pain-related contexts. Immunohistochemical analysis revealed that the number of c-Fos positive oxytocinergic neurons in the paraventricular nucleus of the hypothalamus (PVN) was significantly higher in VPA-treated mice after observational fear learning. Finally, we found that pretreatment with L-368899, an antagonist of the oxytocin receptor, repressed the empathetic behavior in VPA-treated mice. These results suggest that VPA-treated ASD model animals showed increased emotional empathy-like behaviors through the hyperactivation of PVN oxytocinergic neurons for the first time. Further investigation of this hyperactivity will help to identify extrinsic stimuli and the condition which are capable of activation of PVN oxytocinergic neurons and to identify novel approach to enhance oxytocin signaling, which ultimately pave the way to development of novel therapy for ASD.


Subject(s)
Autism Spectrum Disorder , Prenatal Exposure Delayed Effects , Animals , Autism Spectrum Disorder/chemically induced , Behavior, Animal , Disease Models, Animal , Empathy , Female , Humans , Mice , Pregnancy , Prenatal Exposure Delayed Effects/chemically induced , Social Behavior , Valproic Acid/pharmacology
4.
J Pharmacol Sci ; 146(4): 200-205, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34116733

ABSTRACT

Gentle touch such as stroking of the skin produces a pleasant feeling, which is detected by a rare subset of sensory neurons that express Mas-related G protein-coupled receptor B4 (MrgprB4) in mice. We examined small populations of MrgprB4-positive neurons in the trigeminal ganglion and the dorsal root ganglion, and most of these were sensitive to transient receptor potential ankyrin 1 (TRPA1) agonist but not TRPV1, TRPM8, or TRPV4 agonists. Deficiency of MrgprB4 did not affect noxious pain or itch behaviors in the hairless plantar and hairy cheek. Although behavior related to acetone-induced cold sensing in the hind paw was not changed, unpleasant sensory behaviors in response to acetone application or sucrose splash to the cheek were significantly enhanced in Mrgprb4-knockout mice as well as in TRPA1-knockout mice. These results suggest that MrgprB4 in the trigeminal neurons produces pleasant sensations in cooperation with TRPA1, rather than noxious or cold sensations. Pleasant sensations may modulate unpleasant sensations on the cheek via MrgprB4.


Subject(s)
Gene Expression/genetics , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/physiology , Sensation/genetics , Sensation/physiology , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/physiology , TRPA1 Cation Channel/genetics , TRPA1 Cation Channel/physiology , Trigeminal Ganglion/cytology , Animals , Female , Male , Mice, Inbred C57BL , Mice, Knockout , Skin Physiological Phenomena/genetics , TRPA1 Cation Channel/metabolism
5.
Biochem Biophys Res Commun ; 529(3): 590-595, 2020 08 27.
Article in English | MEDLINE | ID: mdl-32736678

ABSTRACT

Intracerebral hemorrhage (ICH) is one of the most severe subtypes of stroke with high morbidity and mortality. Although a lot of drug discovery studies have been conducted, the drugs with satisfactory therapeutic effects for motor paralysis after ICH have yet to reach clinical application. Transient receptor potential vanilloid 4 (TRPV4), a Ca2+-permeable cation channel and activated by hypoosmolarity and warm temperature, is expressed in various cell types. The present study investigated whether TRPV4 would participate in the brain damage in a mouse model of ICH. ICH was induced by intrastriatal treatment of collagenase. Administration of GSK1016790A, a selective TRPV4 agonist, attenuated neurological and motor deficits. The inhibitory effects of the TRPV4 agonist in collagenase-injected WT mice were completely disappeared in TRPV4-KO mice. The TRPV4 agonist did not alter brain injury volume and brain edema at 1 and 3 days after ICH induction. The TRPV4 agonist did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 3 days after ICH induction. Quantitative RT-PCR experiments revealed that the TRPV4 agonist significantly upregulated the expression level of c-fos, a marker of neuronal activity, while the agonist gave no effects on the expression level of cytokines/chemokines at 1 day after ICH induction, These results suggest that stimulation of TRPV4 would ameliorate ICH-induced brain injury, presumably by increased neuronal activity and TRPV4 provides a novel therapeutic target for the treatment for ICH.


Subject(s)
Cerebral Hemorrhage/complications , Leucine/analogs & derivatives , Motor Disorders/prevention & control , Nervous System Diseases/prevention & control , Sulfonamides/pharmacology , TRPV Cation Channels/agonists , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Cerebral Hemorrhage/chemically induced , Collagenases , Disease Models, Animal , Gene Expression/drug effects , Leucine/pharmacology , Male , Mice, Inbred C57BL , Mice, Knockout , Motor Disorders/etiology , Nervous System Diseases/etiology , Proto-Oncogene Proteins c-fos/genetics , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolism
6.
Biochem Biophys Res Commun ; 514(4): 1040-1044, 2019 07 05.
Article in English | MEDLINE | ID: mdl-31097227

ABSTRACT

Microglia are immune cells in the central nervous system (CNS) and essential for homeostasis that are important for both neuroprotection and neurotoxicity, and are activated in a variety of CNS diseases. Microglia aggravate cognitive impairment induced by chronic cerebral hypoperfusion, but their precise roles under these conditions remain unknown. Here, we used PLX3397, a colony-stimulating factor 1 receptor inhibitor, to deplete microglia in mice with chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Cognitive impairment induced 28 days after BCAS was significantly improved in mice fed a diet containing PLX3397. In PLX3397-fed mice, microglia were depleted and white matter injury induced by BCAS was suppressed. In addition, the expression of proinflammatory cytokines, interleukin 6 and tumor necrosis factor alpha, was suppressed in PLX3397-fed mice. Taken together, these findings suggest that microglia play destructive roles in the development of cognitive impairment and white matter injury induced by chronic cerebral hypoperfusion. Thus, microglia represent a potential therapeutic target for chronic cerebral hypoperfusion-related diseases.


Subject(s)
Cerebrovascular Disorders/metabolism , Cognitive Dysfunction/metabolism , Disease Models, Animal , Microglia/metabolism , White Matter/metabolism , Animals , Cerebrovascular Disorders/pathology , Chronic Disease , Cognitive Dysfunction/pathology , Male , Mice , Mice, Inbred C57BL , White Matter/injuries , White Matter/pathology
SELECTION OF CITATIONS
SEARCH DETAIL
...