Minocycline treatment affects astrocyte - microglia - neuron interaction and functional compensation of motor deficits in rat model of combined fluorocitrate and 6-OHDA lesion and early Parkinson's disease

Abstract

Prolonged nervous system inflammation and glia activation are among hallmarks of Parkinsons disease. There are no therapies slowing pathology. Microglia and astrocytes are considered targets for disease modifying strategies. Nigrostriatal neurodegeneration causes locomotor dysfunction but at early stages can be compensated. Interaction between neurons, microglia and astrocytes could be essential for this functional adaptation and neuronal survival in long-term. The aim was to check how microglia activation inhibition affects neuron and astrocyte cell death caused by selective toxins and how it affects locomotion and potential for spontaneous functional compensation of motor deficits at the early stages of Parkinsons disease. In a rat model of fluorocitrate (FC)-induced astrocyte death and microglia activation combined with 6-OHDA selective dopaminergic system neurodegeneration we analyzed anti-inflammatory effect of minocycline on each of the cell type and on functional behavioral output. In result, reduced microglia activation by minocycline probably prevented part of astrocytes from FC-induced cell death. Microglia inhibition caused non-dopaminergic neurodegeneration in a group treated by both neurotoxins but still enhanced compensatory potential to functionally improve walking deficits caused by dopaminergic lesion. It seems that activation of microglia by dying astrocytes vs dying neurons induced varied mechanisms. Inhibition of strong microglia activation could be protective for astrocytes but microglia is also important for neuronal adaptation, therefore suppression of its activation perturbs structural rebuilding during progressive neurodegeneration affecting functional outcome. Understanding the relationship between neuronal death, astrocyte loss of function and microglial response could help to identify new, non-neuronal pharmacological target for healing various neurodegenerative diseases. HighlightsO_LIAstrocyte death affected neuron function but neurodegeneration did not affect astrocyte survival. C_LIO_LIMicroglia was differentially activated by death of astrocytes than by neuron degeneration. C_LIO_LIMinocycline treatment decreased morphological signs of microglia activation, probably protected some astrocytes but negatively affected astrocytes in 6-OHDA lesion group. C_LIO_LIMinocycline treatment despite inducing non-dopaminergic neurodegeneration still enhanced compensatory potential to functionally improve walking after combined 6-OHDA lesion and fluorocitrate-induced astrocyte death. C_LI