pexidartinib and Nerve-Degeneration

The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1. We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry.. We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1. Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.

Topics: Aminopyridines; Animals; Brain; Disease Models, Animal; Female; Macrophages; Male; Mice; Microglia; Nerve Degeneration; Neuronal Ceroid-Lipofuscinoses; Neurons; Pyrroles; Retina; Sex Factors; T-Lymphocytes; Tomography, Optical Coherence

Excitotoxicity is well known in the neuronal death in the brain and is also linked to neuronal damages in the retina. Recent accumulating evidence show that microglia greatly affect excitotoxicity in the brain, but their roles in retina have received only limited attention. Here, we report that retinal excitotoxicity is mediated by microglia. To this end, we employed three discrete methods, that is, pharmacological inhibition of microglia by minocycline, pharmacological ablation by an antagonist for colony stimulating factor 1 receptor (PLX5622), and genetic ablation of microglia using Iba1-tTA::DTA

Topics: Aminopyridines; Animals; Animals, Newborn; Calcium-Binding Proteins; Cell Death; Cells, Cultured; Cytokines; Excitatory Amino Acid Agonists; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Microglia; N-Methylaspartate; Nerve Degeneration; Optic Nerve Injuries; Organic Chemicals; Pyrroles; Retinal Ganglion Cells; Signal Transduction; Transcription Factor Brn-3A; Tumor Necrosis Factor-alpha