Delving into the Latest Updates on Arundic acid with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(2R)-2-propyloctanoic acid, Arocyte Injection, Arundic acid (JAN/INN)

+ [7]

Target

COX-2 x Free radicals x NOS2

Mechanism

COX-2 inhibitors(Cyclooxygenase-2 inhibitors), Free radicals inhibitors, NOS2 inhibitors(Nitric oxide synthase, inducible inhibitors)

Therapeutic Areas

Nervous System DiseasesCardiovascular DiseasesEndocrinology and Metabolic Disease+ [2]

Active Indication-

Inactive Indication

Acute Ischemic StrokeAlzheimer DiseaseAmyotrophic Lateral Sclerosis+ [4]

Originator Organization

Ono Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Ono Pharmaceutical Co., Ltd.

Merck Sharp & Dohme Corp.Ono Pharma USA, Inc.

Drug Highest PhaseDiscontinuedPhase 2/3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC11H22O2

InChIKeyYCYMCMYLORLIJX-SNVBAGLBSA-N

CAS Registry185517-21-9

BACKGROUNDLevodopa-induced dyskinesia (LID) is a common motor complication of levodopa (L-DOPA) treatment for Parkinson's disease (PD). In recent years, the role of astrocytes in LID has increasingly attracted attention.OBJECTIVETo explore the effect of an astrocyte regulator (ONO-2506) on LID in a rat model and the potential underlying physiological mechanism.METHODSUnilateral LID rat models, established by administering 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle through stereotactic injection, were injected with ONO-2506 or saline into the striatum through brain catheterization and were administered L-DOPA to induce LID. Through a series of behavioral experiments, LID performance was observed. Relevant indicators were assessed through biochemical experiments.RESULTSIn the LID model of 6-OHDA rats, ONO-2506 significantly delayed the development and reduced the degree of abnormal involuntary movement in the early stage of L-DOPA treatment and increased glial fibrillary acidic protein and glutamate transporter 1 (GLT-1) expression in the striatum compared to saline. However, there was no significant difference in the improvement in motor function between the ONO-2506 and saline groups.CONCLUSIONSONO-2506 delays the emergence of L-DOPA-induced abnormal involuntary movements in the early stage of L-DOPA administration, without affecting the anti-PD effect of L-DOPA. The delaying effect of ONO-2506 on LID may be linked to the increased expression of GLT-1 in the rat striatum. Interventions targeting astrocytes and glutamate transporters are potential therapeutic strategies to delay the development of LID.

01 May 2023·Acta Neuropathologica

Spinal astrocyte dysfunction drives motor neuron loss in late-onset spinal muscular atrophy

Article

Author: Kleinschnitz, Christoph ; Hezel, Stefanie ; Steffen, Rebecca ; Leo, Markus ; Hagenacker, Tim ; Schara-Schmidt, Ulrike ; Roos, Andreas ; Schmitt, Linda-Isabell ; David, Christina

AbstractSpinal muscular atrophy (SMA) is a progressive neuromuscular disorder caused by a loss of the survival of motor neuron 1 (SMN1) gene, resulting in a loss of spinal motor neurons (MNs), leading to muscle weakness and wasting. The pathogenesis of MN loss in SMA and the selective vulnerability in different cellular populations are not fully understood. To investigate the role of spinal astrocytes in the pathogenesis of late-onset SMA, we used a mouse model in addition to in vitro approaches. Immunostaining, Western blot analysis, small interfering ribonucleic acid (siRNA) transfections, functional assays, enzyme-linked immunosorbent assay (ELISA), behavioral tests, and electrophysiological measurements were performed. Early activation of spinal astrocytes and a reduction of the excitatory amino acid transporter 1 (EAAT1) on postnatal day (P) 20 preceded the loss of spinal MNs in SMA mice occurring on P42. EAAT1 reduction resulted in elevated glutamate levels in the spinal cord of SMA mice at P20 and P42. SMA-like astrocytes generated by siRNA and an ex vivo model of glutamate excitotoxicity involving organotypic spinal cord slice cultures revealed the critical role of glutamate homeostasis in the degeneration of MNs. The pre-emptive administration of arundic acid (AA), as an inhibitor of astrocyte activation, to SMA mice prior to the loss of motor neurons (P28) resulted in elevated EAAT1 protein levels compared to vehicle-treated SMA mice and prevented the increase of glutamate in the spinal cord and the loss of spinal MNs. Furthermore, AA preserved motor functions during behavioral experiments, the electrophysiological properties, and muscle alteration of SMA mice. In a translational approach, we transfected healthy human fibroblasts with SMN1 siRNA, resulting in reduced EAAT1 expression and reduced uptake but increased glutamate release. These findings were verified by detecting elevated glutamate levels and reduced levels of EAAT1 in cerebrospinal fluid of untreated SMA type 2 and 3 patients. In addition, glutamate was elevated in serum samples, while EAAT1 was not detectable. Our data give evidence for the crucial role of spinal astrocytes in the pathogenesis of late-onset SMA, a potential driving force for MN loss by glutamate excitotoxicity caused by EAAT1 reduction as an early pathophysiological event. Furthermore, our study introduces EAAT1 as a potential therapeutic target for additional SMN-independent therapy strategies to complement SMN-enhancing drugs.

01 Apr 2023·Progress in Neuro-Psychopharmacology and Biological Psychiatry

Arundic acid (ONO-2506) downregulates neuroinflammation and astrocyte dysfunction after status epilepticus in young rats induced by Li-pilocarpine

Article

Author: Seady, Marina ; Leal, Miriara B ; Vizuete, Adriana Fernanda K ; Taday, Jéssica ; Moreira, Ana Paula ; Gonçalves, Carlos-Alberto

Astrocytes, the most abundant glial cells, have several metabolic functions, including ionic, neurotransmitter and energetic homeostasis for neuronal activity. Reactive astrocytes and their dysfunction have been associated with several brain disorders, including the epileptogenic process. Glial Fibrillary Acidic Protein (GFAP) and S100 calcium-binding protein B (S100B) are astrocyte biomarkers associated with brain injury. We hypothesize that arundic acid (ONO-2506), which is known as an inhibitor of S100B synthesis and secretion, protects the hippocampal tissue from neuroinflammation and astrocyte dysfunction after status epileptics (SE) induction by Li-pilocarpine in young rats. Herein, we investigated the effects of arundic acid treatment, at time points of 6 or 24 h after the induction of SE by Li-pilocarpine, in young rats. In SE animals, arundic acid was able to prevent the damage induced by Li-pilocarpine in the hippocampus, decreasing neuroinflammatory signaling (reducing IL-1β, COX2, TLR4 and RAGE contents), astrogliosis (decreasing GFAP and S100B) and astrocytic dysfunction (recovering levels of GSH, glutamine synthetase and connexin-43). Furthermore, arundic acid improved glucose metabolism and reduced the glutamate excitotoxicity found in epilepsy. Our data reinforce the role of astrocytes in epileptogenesis development and the neuroprotective role of arundic acid, which modulates astrocyte function and neuroinflammation in SE animals.

100 Deals associated with Arundic acid

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External Link

KEGG	Wiki	ATC	Drug Bank
D06296	-	-	DB05343

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Muscle Weakness	Phase 3	AT	Ono Pharmaceutical Co., Ltd.	01 Nov 2006
Muscle Weakness	Phase 3	NL	Ono Pharmaceutical Co., Ltd.	01 Nov 2006
Muscle Weakness	Phase 3	GB	Ono Pharmaceutical Co., Ltd.	01 Nov 2006
Alzheimer Disease	Phase 3	US	Ono Pharma USA, Inc.	01 Jun 2004
Alzheimer Disease	Phase 3	CA	Ono Pharma USA, Inc.	01 Jun 2004
Parkinson Disease	Phase 3	-	Ono Pharmaceutical Co., Ltd.	01 Jan 2004
Acute Ischemic Stroke	Phase 3	CA	Ono Pharma USA, Inc.	01 Nov 2002
Acute Ischemic Stroke	Phase 3	US	Ono Pharma USA, Inc.	01 Nov 2002
Acute Ischemic Stroke	Phase 3	CA	Ono Pharma USA, Inc.	01 Nov 2002
Acute Ischemic Stroke	Phase 3	US	Ono Pharma USA, Inc.	01 Nov 2002