¶ CCR2 and CCR5 Antagonists for Neurodegeneration
Ccr2 And Ccr5 Antagonists For Neurodegeneration is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Chemokine receptors CCR2 and CCR5 play crucial roles in neuroinflammation by mediating monocyte/microglia recruitment to the central nervous system. CCR2/CCR5 antagonists represent a promising therapeutic approach for reducing harmful neuroinflammation while preserving beneficial immune surveillance.
- CCR2 is expressed on monocytes, macrophages, and microglia
- Ligands include CCL2 (MCP-1), CCL7, CCL8, CCL13
- Activation triggers monocyte recruitment to sites of inflammation
- In neurodegeneration, excessive CCL2-CCR2 signaling drives harmful microglial activation
- CCR5 is expressed on microglia, neurons, and astrocytes
- Ligands include CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES)
- Mediates neurotoxic inflammation in AD, PD, HD, and ALS
- Contributes to leukocyte recruitment across the blood-brain barrier
- Block chemokine binding to prevent receptor activation
- Reduce microglial activation and proliferation
- Decrease pro-inflammatory cytokine production
- Preserve neuroprotective immune functions
- Reduces microglial recruitment around amyloid plaques
- Decreases CCL2/CCR2-mediated neuroinflammation
- May improve cognitive function
- Evidence from APP/PS1 mouse models
- Blocks dopaminergic neuron loss
- Reduces microglial activation in substantia nigra
- Decreases α-synuclein-induced inflammation
- Protective in MPTP and 6-OHDA models
- Reduces mutant huntingtin-induced neuroinflammation
- Decreases microglia activation
- Improves motor function in R6/2 mice
- May slow disease progression
- Reduces microglia-mediated motor neuron injury
- Blocks monocyte infiltration
- May extend survival in SOD1 models
| Agent |
Company |
Development Stage |
References |
| PF-04136309 |
Pfizer |
Phase Ib ( oncology) |
[@PMID1] |
| CCX872 |
ChemoCentryx |
Preclinical |
[@PMID2] |
| RS504393 |
Roche |
Preclinical |
[@PMID3] |
| IN4 |
Incyte |
PreCB334clinical |
[@PMID4] |
| MLN1202 |
Millennium |
Phase II |
[@PMID5] |
| Agent |
Company |
Development Stage |
References |
| Maraviroc |
Pfizer/ViiV |
Approved (HIV), Investigational (AD) |
[@PMID6] |
| Vicriviroc |
Merck |
Phase II (HIV) |
[@PMID7] |
| Aplaviroc |
GSK |
Discontinued (HIV) |
[@PMID8] |
| Cenicriviroc |
Tobira/Allergan |
Phase II (NASH, AD) |
[@PMID9] |
- Cenicriviroc (CVC) - most advanced for neurodegeneration
- Blocks both pathways with single agent
- Currently in Phase II trials for AD
- CCR2 knockout mice show reduced amyloid deposition
- CCR5 deficiency improves memory in AD models
- Dual antagonism more effective than single receptor blockade
- Cenicriviroc Phase II trial in AD (NCT02328872)
- Maraviroc being repurposed for AD (NCT01091614)
- Ongoing trials in MS and ALS
¶ Dosing and Administration
- PF-04136309: 500mg oral BID (under investigation)
- CCX872: Dosing under investigation
- Maraviroc: 300mg oral BID (HIV dose, potential CNS dose TBD)
- Cenicriviroc: 500mg daily
- Headache
- Nausea
- Fatigue
- Elevated liver enzymes (some agents)
- Drug-drug interactions (maraviroc)
- Immune suppression risk
- Long-term safety in CNS diseases unknown
- CCL2 levels in CSF
- Microglial imaging (TSPO PET)
- Peripheral monocyte counts
- Inflammatory cytokines (IL-1β, IL-6, TNF-α)
- Brain-penetrant antagonists
- Biomarker-driven patient selection
- Combination with disease-modifying therapies
- Prevention trials in at-risk individuals
The study of Ccr2 And Ccr5 Antagonists For Neurodegeneration has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- [@PMID:24717640] - PF-04136309 in cancer
- [@PMID:21670273] - CCX872 in inflammation
- [@PMID:12890423] - RS504393 in fibrosis
- [@PMID:18499679] - INCB3344 in inflammation
- [@PMID:19052209] - MLN1202 in MS
- [@PMID:24046261] - Maraviroc in AD models
- [@PMID:15638947] - Vicriviroc pharmacology
- [@PMID:15872081] - Aplaviroc development
- [@PMID:26895669] - Cenicriviroc in NASH/AD