Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model

Abstract

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [18F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies.

Glia-Neurotrophic Factor Relationships: Possible Role in Pathobiology of Neuroinflammation-Related Brain Disorders

“…Furthermore, in further studies, authors have indicated the involvement of CDNF in the reduction of LPS-induced inflammation through the competitive inhibition of Akt phosphorylation and suppression of downstream pathways, including forkhead box protein O1 (FoxO1) and mTOR signaling [ 105 ]. Another study showed that the modulation of inflammatory responses caused by CDNF is not only by decreasing microglia/macrophage recruitment but also regulating its polarization and enhancing M2 subset polarization [ 121 ]. Degeneration of dopaminergic neurons can be caused by several processes, among which the oligomerization of α-synuclein and the deposition of these forms of α-synuclein in the cytoplasm of neurons play a key role.…”

“…Based on the promising results of animal studies [ 64 , 101 , 109 , 113 , 121 , 131 ], it was hypothesized that NTFs could be a potential regenerative tool in inflammatory and degenerative conditions of the CNS. Each NFT has its unique profile of action on specific subsets of neurons to ensure their optimal function.…”

CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson’s disease

“…Inflammatory cytokines produced by activated microglia participate in the progression of PD pathogenesis (154). Increasing evidence suggests that CDNF and MANF possess immunomodulatory functions that contribute to their cytoprotective and neuroprotective properties (56,88,94,111,155). Although MANF was originally isolated as a secreted factor from the culture medium of a mesencephalic astrocyte cell line (18), it was noted that in normal conditions MANF expression is low in brain glial cells but can be induced upon glial cell activation in stress conditions (156).…”

“…Therapeutic efficacy of CDNF may depend on several factors such as the severity of PD model and the route of administration. After injections of 6-OHDA into the MFB, CDNF has not achieved neuronal restoration in rodent PD models ( 111 , 112 ). CDNF could improve only apomorphine-induced rotational asymmetry ( 112 ).…”

“…These data suggest that CDNF therapy would be more suitable for early-stage PD patients. While in most preclinical studies CDNF is delivered intrastriatally, these two studies used different routes for the delivery: the intracerebral ventricle ( 111 ) and the SN ( 112 ). In a naïve rat brain, CDNF injected to the SN is not transported to the striatum, indicating that anterograde transport of CDNF is not active, in contrast to the observed active retrograde CDNF transport ( 114 ).…”