PLX5622 is a highly selective brain penetrant and orally active CSF1R inhibitor (IC₅₀=0.016 µM; K_i=5.9 nM). PLX5622 allows for extended and specific microglial cell elimination, preceding and during pathology development. Additionally, PLX5622 demonstrates desirable PK properties in various animals. It exhibits F% values of 59%, 95%, and 89%, respectively in mice, rats (male), and rats (female), respectively.

PLX5622 is a potential and potent Microglia depletion agent.

5xFAD mice display increased numbers of microglia/myeloid cells at both 4-7 months of age, PLX5622-formulated chow (1200 ppm; 10–24 weeks) leads to almost complete microglial elimination (97–100% reduction). Besides, The absence of microglia for 24 weeks in wild-type mice does not induce any measurable negative effects in animal behavior, including tests of anxiety and motor function.

PLX5622-formulated chow (1200 ppm; 10 weeks) eliminated > 99% of microglia in the cortex in both wild and 5XFAD mice, but a fraction of cells remained in the thalamus. In the absence of microglia, there exhibits a stark lack of dense-core plaques within cortical regions ( retrosplenial (RS) and somatosensory (SS) cortices). Plaques are also formed within the thalamus but are again predominantly associated with surviving microglia. These results suggest that microglia may be critical regulators of plaque formation and that few surviving microglial cells are sufficient to facilitate some degree of plaque formation (i.e., as seen in the thalamus).

PLX5622 (50 mg/kg; intraperitoneal injection; once (neonatal rat) or twice (adult rat) a day; for a total of 14 days) depletes microglia to > 90% by 7 days. After 14 days of PLX5622 treatment, microglia are depleted by > 96% in both neonates and adults while preserving baseline astrocyte quantity. Furthermore, 50 mg/kg is sufficient for neonatal microglia depletion, adult depletion requires injections twice daily. The single daily injection of 0.65% PLX5622 suspended in 5% dimethyl sulfoxide and 20% Kolliphor RH40 in 0.01 M PBS.

In conclusion, PLX5622 is a potent CSF1R inhibitor. It is widely used in Microglia Clearance.

Reference:

[1] Spangenberg E, et al.  Nat Commun. 2019 Aug 21;10(1):3758.

[2] Andrew J. Riquier, et al. Brain, Behavior, & Immunity-Health, Volume 1, 2020, 100010, ISSN 2666-3546.