Delving into the Latest Updates on PLX-5622 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PLX 5622, PLX5622

Target

CSF-1R

Action

antagonists

Mechanism

CSF-1R antagonists(Colony stimulating factor 1 receptor antagonists)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesOther Diseases

Active Indication

Multiple Sclerosis, Primary Progressive

Inactive Indication

Rheumatoid Arthritis

Originator Organization

Daiichi Sankyo Co., Ltd.

Active Organization

University of Manitoba

Inactive Organization

Plexxikon, Inc.

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC21H19F2N5O

InChIKeyNSMOZFXKTHCPTQ-UHFFFAOYSA-N

CAS Registry1303420-67-8

JOURNAL/nrgr/04.03/01300535-202601000-00040/figure1/v/2025-03-30T110608Z/r/image-tiff Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited. Microglia is the resident immune cells of the central nervous system, play a critical role in spinal cord injury. Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors. However, excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars, which hinder axonal regeneration. Despite this, the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood. To elucidate the role of microglia in spinal cord injury, we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia. We observed that sustained depletion of microglia resulted in an expansion of the lesion area, downregulation of brain-derived neurotrophic factor, and impaired functional recovery after spinal cord injury. Next, we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia. We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function. Additionally, brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury. Furthermore, through using specific transgenic mouse lines, TMEM119, and the colony-stimulating factor 1 receptor inhibitor PLX73086, we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages. In conclusion, our findings suggest the critical role of microglia in the formation of protective glial scars. Depleting microglia is detrimental to recovery of spinal cord injury, whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.

01 Nov 2025·NEUROBIOLOGY OF DISEASE

Astrocyte-microglia crosstalk in the hippocampus mediates cognitive impairments induced by chronic intermittent hypoxia

Article

Author: Zhai, Ming-Rui ; Wu, Zhen-Huan ; Xiao, Lei ; Pan, Jie ; Wang, Yu-Rong ; Liu, Yue-Hua ; Ren, Long

Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a common systemic disease with a high-risk factor for developing cognitive impairment. However, the possible mechanism(s) underlying the cognitive function impairment in CIH remain largely unknown. In this study, our results reveal that 8-week CIH reliably induces significant cognitive impairment, synaptic deficits, and pronounced microglial activation characterized by excessive synaptic phagocytosis. Pharmacological depletion of microglia using PLX5622 ameliorated these CIH-induced impairments. Furthermore, CIH enhanced the interaction between activated astrocytes and microglia, accompanied by upregulation of complement C3 in astrocytes and C3aR in microglia. Notably, blocking C3aR with SB290157 attenuated microglial overactivation, reduced aberrant synaptic engulfment, and improved cognitive performance in CIH-exposed mice. Collectively, these findings demonstrate that C3/C3aR-mediated astrocyte-microglia crosstalk contributes to CIH-induced cognitive dysfunction by activating microglia to excessive phagocytosis of synapses.

01 Oct 2025·BRAIN BEHAVIOR AND IMMUNITY

Microglia depletion in a mouse model of prenatal and postnatal immune activation

Article

Author: Del Castillo, Ignacio ; Ciano Albanese, Naomi ; Ragaglia, Giulia ; Ricceri, Laura ; De Simone, Roberta ; Castellano, Giulia ; Griguoli, Marilena ; Ajmone-Cat, Maria Antonietta

Risk for neurodevelopmental disorders can be related to early immune stimulations and altered brain microglial functions. Here we investigated the behavioural and electrophysiological effects of microglia depletion in a mouse model of developmental immune activation. C57BL/6J pregnant mice were exposed on gestational day 12.5 to polyinosinic:polycytidylic acid (Poly I:C), subsequently, on postnatal day 9, offspring was further treated with lipopolysaccharide (LPS). At weaning, offspring was exposed throughout adolescence (4 weeks) to either a diet containing Colony Stimulating Factor-1 receptor inhibitor (PLX5622, PLX) to reduce microglia, or standard diet. Hence, we assessed i) explorative and anxiety-like responses, social responsiveness and cognitive abilities between 7^th and 8^th postnatal week; ii) synaptic transmission and neuroinflammatory and microglial molecular markers in the medial prefrontal cortex (mPFC) and hippocampus (HP) at the end of treatment (8^th postnatal week). EIA condition reduced locomotor activity and impaired discrimination between a familiar and a novel social stimulus (social novelty response) only in male mice. Also, PLX treatment selectively affected the same social novelty response in males (both saline and EIA) and in EIA females, intriguingly sparing saline females. Unexpectedly, EIA condition per se did not affect spontaneous excitatory and inhibitory synaptic transmission in both mPFC and HP, whereas EIA combined with PLX reduced inhibitory transmission in males (both mPFC and HP) and neuron excitability in both male and female mPFC. Interestingly, PLX had per se sex- and region- specific effects increasing inhibitory transmission in female mPFC and decreasing excitatory transmission in male HP. Molecular data, beside a robust downregulation of microglia markers in PLX diet groups, also showed that EIA condition increased interleukin-6 (il-6) expression in EIA males in both mPFC and HP, and elevated il-1β levels in both sexes in mPFC and in male HP. Overall, these findings indicate that males have an increased vulnerability to the long-term behavioural and inflammatory effects of the EIA condition, and are more likely to exhibit behavioural and electrophysiological changes in response to microglia depletion.

100 Deals associated with PLX-5622

Login to view more data

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	Phase 1	United States	Plexxikon, Inc.	15 Nov 2013
Rheumatoid Arthritis	Phase 1	United States	Plexxikon, Inc.	01 May 2011
Multiple Sclerosis, Primary Progressive	Preclinical	Canada	University of Manitoba	30 May 2023