Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model

Abstract

Increasing evidence supports a decisive role for inflammation in the neurodegenerative process of Parkinson's disease (PD). The immune response in PD seems to involve, not only microglia, but also other immune cells infiltrated into the brain. Indeed, we observed here the infiltration of macrophages, specifically CD163ϩ macrophages, into the area of neurodegeneration in the 6-hydroxydopamine (6-OHDA) PD model. Therefore, we investigated the therapeutic potential of the infiltrated CD163ϩ macrophages to modulate local microglia in the brain to achieve neuroprotection. To do so, we designed liposomes targeted for the CD163 receptor to deliver dexamethasone (Dexa) into the CD163ϩ macrophages in the 6-OHDA PD model. Our data show that a fraction of the CD163-targeted liposomes were carried into the brain after peripheral intravenous injection. The 6-OHDA-lesioned rats that received repeated intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia expressing major histocompatibility complex II. Therefore, rats receiving CD163-targeted liposomes with Dexa were partially protected against 6-OHDA-induced dopaminergic neurodegeneration, which correlated with a distinctive microglia response. Altogether, our data support the use of macrophages for the modulation of brain neurodegeneration and specifically highlight the potential of CD163-targeted liposomes as a therapeutic tool in PD.

Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood‐brain barrier dysfunction and seizure progression

“…Interestingly, dexamethasone reduced the number of seizures after pilocarpine‐induced SE in rats and improved BBB integrity. In addition, rats that received CD163‐targeted liposomes were partially protected against 6‐hydroxydopamine–induced dopaminergic neurodegeneration . Furthermore, glucocorticosteroids reduced the occurrence of seizures in pediatric drug‐resistant epilepsy patients in the same study .…”

“…In addition, rats that received CD163-targeted liposomes were partially protected against 6-hydroxydopamineinduced dopaminergic neurodegeneration. 39 Furthermore, glucocorticosteroids reduced the occurrence of seizures in pediatric drug-resistant epilepsy patients in the same study. 10 Limiting the entry of blood monocytes via blockade of CCL2 synthesis or its receptor CCR2 reduced lipopolysaccharideinduced seizures, 31 and attenuated BBB disruption and neuronal damage after pilocarpine-induced SE.…”

Updates on immunity and inflammation in Parkinson disease pathology

“…Glucocorticoids are also a potent antiinflammatory drug and could be used in PD therapeutics. Studies have shown the protective effect of glucocorticoid in experimental models of PD (Jiang et al, 2015;Tentillier et al, 2016). Dexamethasone, a synthetic glucocorticoid receptor ligand, and genistein, an isoflavone, protect the neuronal SK-N-SH cells against 6-OHDA-induced apoptosis by upregulating the Bax and downregulating the Bcl proteins (Gao, Xie, Wong, & Chen, 2012).…”

Stress and corticosterone alter synaptic plasticity in a rat model of Parkinson’s disease

“…Accordingly, low levels of CORT supplementation in ADX-treated animals has been shown to enhance neuroprotection (Qiu et al, 2012) which may occur through moderating the inflammatory response associated with 6-OHDA-induced neurodegeneration which can also be seen in human PD (Theodore and Maragos, 2015). The immune response after 6-OHDA lesion involves activated microglia, but also infiltration of other immune cells such as macrophages (Tentillier et al, 2016). Consequently, GC administration may promote neuroprotection through their well-documented anti-inflammatory effects (Silva et al, 2009; Tentillier et al, 2016).…”

“…The immune response after 6-OHDA lesion involves activated microglia, but also infiltration of other immune cells such as macrophages (Tentillier et al, 2016). Consequently, GC administration may promote neuroprotection through their well-documented anti-inflammatory effects (Silva et al, 2009; Tentillier et al, 2016). In addition, neurotrophic factor expression in striatum, including brain-derived neurotrophic factor, may also occur independently of GR-mediated mechanisms (Schulte-Herbruggen et al, 2006).…”