Microglia PKM2 Mediates Neuroinflammation and Neuron Loss in Mice Epilepsy through the Astrocyte C3-Neuron C3R Signaling Pathway

Brain Sciences, Journal Year: 2023, Volume and Issue: 13(2), P. 262 - 262

Published: Feb. 3, 2023

Epilepsy is a neurological disease and approximately 30% of patients have failed to respond current anti-epilepsy drugs. The neuroinflammation mechanism has raised increasing concerns been regarded as the novel treatment strategy in epilepsy, but target molecules require further research. Pyruvate kinase isoform 2 (PKM2) well studied peripheral inflammation, its role epilepsy remains unclear. We knocked down microglia PKM2 hippocampus using stereotaxic adeno-associated virus (AAV) microinjection established pilocarpine-induced status epilepticus (PISE) model. Racine score was used evaluate seizure grade. Next, we WB, Multiplex tyramide signal amplification (TSA) staining other methods determine complement component 3 (C3)-C3aR interaction primary microglia. Results showed that knockdown reduced grade rescued neuron loss. Mechanistically, inhibited activation inflammation factor secretion through suppressing p65 expression phosphorylation. C1q, TNF-α, IL-1α were responsible for decreased astrocyte C3 following damage caused by C3-C3aR interaction. Our data suggest inhibition ameliorates loss which provides an attractive intervention damaged neuron-glia crosstalk epilepsy.

Language: Английский

---

Kir6.1/K-ATP channel in astrocytes is an essential negative modulator of astrocytic pyroptosis in mouse model of depression

Theranostics, Journal Year: 2022, Volume and Issue: 12(15), P. 6611 - 6625

Published: Jan. 1, 2022

Rationale: Astrocyte dysfunction is one of the important pathological mechanisms depression. Stress contributes to onset As metabolic stress sensor, Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) prominently expressed in astrocytes. However, involvement Kir6.1/K-ATP depression remains obscure. Methods: Astrocyte-specific Kir6.1 knockout mice were used prepare two mouse models explore role astrocytic Primary astrocytes cultured reveal underlying mechanism for Kir6.1-regulated pyroptosis. Results: We identified that chronic reduced expression hippocampus mice. further observed astrocyte-specific induced depressive-like behaviors Moreover, we found deletion increased NLRP3-mediated pyroptosis response stress. Mechanistically, associated with NLRP3, and this interaction prevented assembly activation NLRP3 inflammasome, thereby inhibition More importantly, VX-765, an effective selective inhibitor could reverse rescue deterioration Conclusions: Our findings illustrate essential negative modulator plays a crucial suggest may be promising therapeutic target

Language: Английский

---

Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(5), P. 1258 - 1276

Published: June 3, 2024

The central nervous system, information integration center of the body, is mainly composed neurons and glial cells. neuron one most basic important structural functional units with sensory stimulation excitation conduction functions. Astrocytes microglia belong to cell family, which main source cytokines represents defense system system. Nerve cells undergo neurotransmission or gliotransmission, regulates neuronal activity via ion channels, receptors, transporters expressed on nerve membranes. Ion large transmembrane proteins, play crucial roles in maintaining homeostasis. These channels are also for control membrane potential secretion neurotransmitters. A variety cellular functions life activities, including regulation generation excitation, occurrence receptor potential, heart pulsation, smooth muscle peristalsis, skeletal contraction, hormone secretion, closely related associated passive transport. Two types potassium calcium various neurological disorders, Alzheimer’s disease, Parkinson’s epilepsy. Accordingly, drugs that can affect these have been explored deeply provide new directions treatment disorders. In this review, we focus different their involvement disorders such as depression, epilepsy, autism, rare We describe several clinical target could be used treat concluded there few improve pathology diseases by acting ions. Although a novel ion-channel-specific modulators discovered, meaningful therapies largely not yet realized. lack target-specific drugs, requirement cross blood–brain barrier, exact underlying mechanisms all need further attention. This review aims explain urgent problems research progress comprehensive aiming arouse community’s interest development channel-targeting identification therapeutic targets increase cure rate reduce adverse reactions other systems.

Language: Английский

---

Astrocyte-neuron communication through the complement C3-C3aR pathway in Parkinson’s disease

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

---

Glial Cell Crosstalk in Parkinson's Disease: Mechanisms, Implications, and Therapeutic Strategies

Fundamental Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

---

Natural products target pyroptosis for ameliorating neuroinflammation: A novel antidepressant strategy

Phytomedicine, Journal Year: 2025, Volume and Issue: 138, P. 156394 - 156394

Published: Jan. 14, 2025

Language: Английский

---

C3/C3aR Bridges Spinal Astrocyte‐Microglia Crosstalk and Accelerates Neuroinflammation in Morphine‐Tolerant Rats

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 1, 2025

Communication within glial cells acts as a pivotal intermediary factor in modulating neuroimmune pathology. Meanwhile, an increasing awareness has emerged regarding the detrimental role of and neuroinflammation morphine tolerance (MT). This study investigated influence crosstalk between astrocyte microglia on evolution tolerance. Sprague-Dawley rats were intrathecally treated with twice daily for 9 days to establish morphine-tolerant rat model. Tail-flick latency test was performed identify analgesic effect morphine. The microglia, C3-C3aR axis elucidated by real-time quantitative polymerase chain reaction, Western blot, immunofluorescence. Chronic treatment notably promoted activation upregulated production proinflammatory mediators (interleukin-1 alpha (IL-1α), tumor necrosis (TNFα), complement component 1q (C1q)). Simultaneously, it programed astrocytes pro-inflammatory phenotype (A1), which mainly expresses 3 (C3) serping1. PLX3397 (a colony-stimulating 1 receptor (CSF1R) inhibitor), Compstain C3 inhibitor) SB290157(a C3aR antagonist) could reverse above pathological process alleviate different extents. Our findings amplifier microglia-astrocyte crosstalk, node therapeutic intervention

Language: Английский

---

Direct Effects of Antipsychotics on Potassium Channels

Biochemical and Biophysical Research Communications, Journal Year: 2025, Volume and Issue: 749, P. 151344 - 151344

Published: Jan. 18, 2025

Language: Английский

---

Upregulating mTOR/S6 K Pathway by CASTOR1 Promotes Astrocyte Proliferation and Myelination in Gpam−/−-induced mouse model of cerebral palsy

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Language: Английский

---

Complement Molecule C3a Exacerbates Early Brain Injury After Subarachnoid Hemorrhage by Inducing Neuroinflammation Through the C3aR-ERK-P2X7-NLRP3 Inflammasome Signaling Axis

Inflammation, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 11, 2024

Language: Английский

---