CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease

“The protein contents were determined in pellet fractions by the method described by Lowry [45], and expressed as ng/g wet weight of tissue (ng/g WW).”

“Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, and is characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) [1].”

“Kyrkanides S, O’Banion MK, Whiteley PE, Daeschner JC, Olschowka JA: Enhanced glial activation and expression of specific CNS inflammationrelated molecules in aged versus young rats following cortical stab injury.”

“Unbiased stereological estimates of DA (TH-positive cell) neuron numbers were performed using StereoInvestigator analysis software (MicroBrightField, Williston, VT), combined with a Nikon Eclipse E600 microscope, and the optical fractionator method according to previously published reports [42,43].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“Rotational behaviour was tested in rotometer bowls [47].”

“To further confirm a relationship between CD200CD200R signalling and neuroinflammation in PD, we assayed several molecules that would be secreted by activated microglia in the proinflammatory stage [10,55-59].”

“To further confirm a relationship between CD200CD200R signalling and neuroinflammation in PD, we assayed several molecules that would be secreted by activated microglia in the proinflammatory stage [10,55-59].”

“Activated microglia are found in the SN of mesencephalon in the brain of PD patients [5-8] and of parkinsonian animal models [9-13].”

“In addition, preventing CD200CD200R interactions with CD200R-blocking antibodies also induces augmented microglial activation in EAE rats [32,33].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“Activated microglia are found in the SN of mesencephalon in the brain of PD patients [5-8] and of parkinsonian animal models [9-13].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“[71], Depino AM et al.”

“Beside this, the small volume of the SN makes it hard to inject any reagent precisely into the SN [80,81].”

“However, emerging investigations suggest that multiple factors, both genetic and acquired, contribute to the loss of dopaminergic cells in the substantia nigra (SN) of these patients [2-4].”

“To further confirm a relationship between CD200CD200R signalling and neuroinflammation in PD, we assayed several molecules that would be secreted by activated microglia in the proinflammatory stage [10,55-59].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“To further confirm a relationship between CD200CD200R signalling and neuroinflammation in PD, we assayed several molecules that would be secreted by activated microglia in the proinflammatory stage [10,55-59].”

“Kyrkanides S, O’Banion MK, Whiteley PE, Daeschner JC, Olschowka JA: Enhanced glial activation and expression of specific CNS inflammationrelated molecules in aged versus young rats following cortical stab injury.”

“Activated microglia are found in the SN of mesencephalon in the brain of PD patients [5-8] and of parkinsonian animal models [9-13].”

“To further confirm a relationship between CD200CD200R signalling and neuroinflammation in PD, we assayed several molecules that would be secreted by activated microglia in the proinflammatory stage [10,55-59].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“Interestingly, decreased expression of CD200 and CD200R have also been found in hippocampus and inferior temporal gyrus of patients suffering from Alzheimer’s disease [36].”

“According to previous studies, the bolus administration of any substance into cerebrum may cause mechanical damage to neurons [73,74] and subsequent adjacent activation of microglia [74-79].”

“Boundaries in the SN were defined according to previously defined anatomical analysis in the rat [44] and cells were counted from every sixth 25-μm section (~24 sections) along the entire SN (to ensure coefficient of errors <0.”

“However, emerging investigations suggest that multiple factors, both genetic and acquired, contribute to the loss of dopaminergic cells in the substantia nigra (SN) of these patients [2-4].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“Activated microglia are found in the SN of mesencephalon in the brain of PD patients [5-8] and of parkinsonian animal models [9-13].”

“Beside this, the small volume of the SN makes it hard to inject any reagent precisely into the SN [80,81].”

“To further confirm a relationship between CD200CD200R signalling and neuroinflammation in PD, we assayed several molecules that would be secreted by activated microglia in the proinflammatory stage [10,55-59].”

“CD200R, an important inhibitory receptor present on microglia [23], actively maintains microglia in a quiescent state through its interaction with CD200, a transmembrane glycoprotein expressed on neurons [24-29].”

“Activated microglia are found in the SN of mesencephalon in the brain of PD patients [5-8] and of parkinsonian animal models [9-13].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“Down-regulation of CD200 has also been detected in brain of multiple sclerosis (MS) patients [37].”

“Molecules related to neuroinflammation, such as tumor necrosis factor-alpha (TNF-a), IL-6, IL-1b, interferongamma (IFN-g), and superoxide, have been found colocalized with microglia in brain, and in cerebrospinal fluid and serum of PD patients as well [6,7,14-22].”

“There is no report about the expression levels of CD200R or CD200 in patients with prion disease, but activated microglia are thought to be related to upregulation of CD200R4 in a mouse model of prion disease [70].”

“Conversely, CD200 mice receiving exogenous CD200R agonist, including CD200 antigen [34] or an agonist anti-CD200R antibody [35], are resistant to the induction of experimental autoimmune uveoretinitis (EAU).”

“According to previous studies, the bolus administration of any substance into cerebrum may cause mechanical damage to neurons [73,74] and subsequent adjacent activation of microglia [74-79].”

“CD200R, an important inhibitory receptor present on microglia [23], actively maintains microglia in a quiescent state through its interaction with CD200, a transmembrane glycoprotein expressed on neurons [24-29].”

“We also found that blocking CD200-CD200R engagement dramatically exacerbates dopaminergic neurodegeneration in a primary neuron/ microglia co-culture system [41].”

“According to previous studies, the bolus administration of any substance into cerebrum may cause mechanical damage to neurons [73,74] and subsequent adjacent activation of microglia [74-79].”

“Liu Y, Bando Y, Vargas-Lowy D, Elyaman W, Khoury SJ, Huang T, Reif K, Chitnis T: CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.”

“Moreover, this increased microglial response is substantiated by enhanced expression of Class II major histocompatibility complex (MHC II), TNF-a and inducible nitric oxide synthetase (iNOS) [31].”

“Liu Y, Bando Y, Vargas-Lowy D, Elyaman W, Khoury SJ, Huang T, Reif K, Chitnis T: CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.”

“These results suggest that a deficient CD200-CD200R system may be involved in the progression of various neurological disorders [38,39].”

“Phaseolus vulgarisleucoagglutinin and biocytin, injected into striatum, can later be found in substantia nigra pars reticulate (SNpr) and substantia nigra pars compacta (SNpc) in squirrel monkeys [82].”

“[32], and later by many other investigators [33,41,48-51].”

“[32], and later by many other investigators [33,41,48-51].”

“However there are two different CD200Rs in mice [54,60,63,64]; an inhibitory receptor CD200R1 [48,65-68] and an activating receptor CD200R2-4 [69].”

“In addition, preventing CD200CD200R interactions with CD200R-blocking antibodies also induces augmented microglial activation in EAE rats [32,33].”

“According to previous studies, the bolus administration of any substance into cerebrum may cause mechanical damage to neurons [73,74] and subsequent adjacent activation of microglia [74-79].”

“0 turns/min could be regarded as successfully induced hemiparkinsonian rats [43,52].”

“CD200R, an important inhibitory receptor present on microglia [23], actively maintains microglia in a quiescent state through its interaction with CD200, a transmembrane glycoprotein expressed on neurons [24-29].”

“Kyrkanides S, O’Banion MK, Whiteley PE, Daeschner JC, Olschowka JA: Enhanced glial activation and expression of specific CNS inflammationrelated molecules in aged versus young rats following cortical stab injury.”

“These results suggest that a deficient CD200-CD200R system may be involved in the progression of various neurological disorders [38,39].”

“According to previous studies, the bolus administration of any substance into cerebrum may cause mechanical damage to neurons [73,74] and subsequent adjacent activation of microglia [74-79].”

“Liu Y, Bando Y, Vargas-Lowy D, Elyaman W, Khoury SJ, Huang T, Reif K, Chitnis T: CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.”

“However there are two different CD200Rs in mice [54,60,63,64]; an inhibitory receptor CD200R1 [48,65-68] and an activating receptor CD200R2-4 [69].”

“253 Besides, CB1 receptors are abundant in neurons, while CB2 receptors are primarily expressed in microglia in the brain.”

“Likewise, dysfunction of CD200-CD200R signaling also increases the activation of microglia and exacerbates the degeneration of DA neurons in rat PD models [30, 31].”

“In rat PD models, both deficiency CX3CL1 or CX3CR1 as well as the dysfunction of CD200CD200R signaling have been shown to increase microglial activation and the degeneration of DA neurons (Wang et al., 2011; Zhang et al., 2011).”