Doxycycline restrains glia and confers neuroprotection in a 6‐OHDA Parkinson model

Abstract

Neuron-glia interactions play a key role in maintaining and regulating the central nervous system. Glial cells are implicated in the function of dopamine neurons and regulate their survival and resistance to injury. Parkinson's disease is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, decreased striatal dopamine levels and consequent onset of extrapyramidal motor dysfunction. Parkinson's disease is a common chronic, neurodegenerative disorder with no effective protective treatment. In the 6-OHDA mouse model of Parkinson's disease, doxycycline administered at a dose that both induces/represses conditional transgene expression in the tetracycline system, mitigates the loss of dopaminergic neurons in the substantia nigra compacta and nerve terminals in the striatum. This protective effect was associated with: (1) a reduction of microglia in normal mice as a result of doxycycline administration per se; (2) a decrease in the astrocyte and microglia response to the neurotoxin 6-OHDA in the globus pallidus and substantia nigra compacta, and (3) the astrocyte reaction in the striatum. Our results suggest that doxycycline blocks 6-OHDA neurotoxicity in vivo by inhibiting microglial and astrocyte expression. This action of doxycycline in nigrostriatal dopaminergic neuron protection is consistent with a role of glial cells in Parkinson's disease neurodegeneration. The neuroprotective effect of doxycycline may be useful in preventing or slowing the progression of Parkinson's disease and other neurodegenerative diseases linked to glia function.

L‐alpha‐aminoadipic acid restricts dopaminergic neurodegeneration and motor deficits in an inflammatory model of Parkinson’s disease in male rats

“…Co‐injection of intra‐nigral L‐AAA neutralized the LPS‐induced reactive GFAP + astrogliosis and exorbitant S100β production which correlated with a sizeable repression in dopaminergic neuronal loss and nigrostriatal dopamine depletion (Figure a–f). Our findings are similar to those of Lazzarini et al () who have shown that 6‐hydroxydopamine (6‐OHDA)‐induced motor dysfunction and dopaminergic neuropathology in the SNpc & striatum are associated with increases in GFAP + reactive astrocytes when assessed 25 days post unilateral striatal lesioning, whereas the neuroprotection conferred on foot of treatment with the antibiotic doxycycline is associated with a reduction in the nigral & striatal astroglial response to 6‐OHDA. L‐AAA relieves the nigrostriatal dopaminergic tract from the astroglial response to LPS, preventing the dopamine loss and facilitating improvements in motor function.…”

HIV‐1Tat regulation of dopamine transmission and microglial reactivity is brain region specific

“…Previous reports have shown reductions in microglia using staining for Iba1 and Mac-1 antigens in the mouse brain after weeks of doxycycline administration implying that the use of this antibiotic could confound studies of brain inflammation (Lazzarini et al, 2013; Sultan et al, 2013). We have therefore considered the possibility that 7 days of 100 mg/kg doxycycline administration might affect the number and morphology of microglia and possibly TH immunoreactivity in the SNc.…”

Differential response of pineal microglia to surgical versus pharmacological stimuli

“…In adult rats, we disrupted the sympathetic innervation of the PG by either performing a bilateral surgical removal of the SCG (SCGx), or by performing a decentralization procedure of the SCG (SCGd), which severed the connection between the ganglion and the sympathetic nerve trunk but left the SCG and its efferent nerves intact (Hartley et al, 2015;Savastano et al, 2010). We also challenged separate groups of adult rats pharmacologically, either via intraperitoneal (IP) administration of gramnegative bacteria wall components, lipopolysaccharides (LPS) (Ajmone-Cat et al, 2003;Cacci et al, 2008;Cunningham, Martinez-Cerdeño, & Noctor, 2013;Jiang-Shieh et al, 2005;Li et al, 2007;Xie et al, 2017), or by IP administration of the antibiotic doxycycline (DOX), which is an inhibitor of microglial function (Jantzie, Cheung, & Todd, 2005;Lazzarini et al, 2013;Santa-Cecilia et al, 2016;Sultan, Gebara, & Toni, 2013;Yrjanheikki, Keinanen, Pellikka, Hokfelt, & Koistinaho, 1998). The manipulations applied here stem from our current understanding about the tight interplay between microglia and neuronal activity, and between microglia and inflammatory elements induced by peripheral insults, such as bacterial infections (Catorce & Gevorkian, 2016;Colonna & Butovsky, 2017;Wake et al, 2013;Xie et al, 2017).…”