Spinal Cord Brain Derived Neurotrophic Factor (BDNF) Responsive Cells in an Experimental Autoimmune Encephalomyelitis (EAE) Model of Multiple Sclerosis (MS): Implications in Myelin Repair

Zhu, Wenjun; Acosta, Crystal; MacNeil, Brian; Klonisch, Thomas; Cortés, Claudia; Doupe, Malcolm; Gong, Yuewen; Namaka, Michael

doi:10.5171/2014.612406

Cited by 6 publications

(6 citation statements)

References 75 publications

(82 reference statements)

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“…Our findings are aligned with reports by others of unchanged mRNA levels for BDNF and TrkB in the CNS of EAE mice exhibiting clinical disease (Zhu et al. , ).…”

Section: Discussionsupporting

confidence: 93%

Antiallodynic effects of alpha lipoic acid in an optimized RR‐EAE mouse model of MS‐neuropathic pain are accompanied by attenuation of upregulated BDNF‐TrkB‐ERK signaling in the dorsal horn of the spinal cord

Khan

Gordon

Woodruff

et al. 2015

Pharmacology Res & Perspec

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Neuropathic pain may affect patients with multiple sclerosis (MS) even in early disease. In an experimental autoimmune encephalomyelitis (EAE)-mouse model of MS, chronic alpha lipoic acid (ALA) treatment reduced clinical disease severity, but MS-neuropathic pain was not assessed. Hence, we investigated the pain-relieving efficacy and mode of action of ALA using our optimized relapsing-remitting (RR)-EAE mouse model of MS-associated neuropathic pain. C57BL/6 mice were immunized with MOG35-55 and adjuvants (Quil A and pertussis toxin) to induce RR-EAE; sham-mice received adjuvants only. RR-EAE mice received subcutaneous ALA (3 or 10 mg kg−1 day−1) or vehicle for 21 days (15–35 d.p.i.; [days postimmunization]); sham-mice received vehicle. Hindpaw hypersensitivity was assessed blinded using von Frey filaments. Following euthanasia (day 35 d.p.i.), lumbar spinal cords were removed for immunohistochemical and molecular biological assessments. Fully developed mechanical allodynia in the bilateral hindpaws of vehicle-treated RR-EAE mice was accompanied by marked CD3+ T-cell infiltration, microglia activation, and increased brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling in the dorsal horn of the lumbar spinal cord. Consequently, phospho-ERK, a marker of central sensitization in neuropathic pain, was upregulated in the spinal dorsal horn. Importantly, hindpaw hypersensitivity was completely attenuated in RR-EAE mice administered ALA at 10 mg kg−1 day−1 but not 3 mg kg−1 day−1. The antiallodynic effect of ALA (10 mg kg−1 day−1) was associated with a marked reduction in the aforementioned spinal dorsal horn markers to match their respective levels in the vehicle-treated sham-mice. Our findings suggest that ALA at 10 mg kg−1 day−1 produced its antiallodynic effects in RR-EAE mice by reducing augmented CD3+ T-cell infiltration and BDNF-TrkB-ERK signaling in the spinal dorsal horn.

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“…Our findings are aligned with reports by others of unchanged mRNA levels for BDNF and TrkB in the CNS of EAE mice exhibiting clinical disease (Zhu et al. , ).…”

Section: Discussionsupporting

confidence: 93%

Antiallodynic effects of alpha lipoic acid in an optimized RR‐EAE mouse model of MS‐neuropathic pain are accompanied by attenuation of upregulated BDNF‐TrkB‐ERK signaling in the dorsal horn of the spinal cord

Khan

Gordon

Woodruff

et al. 2015

Pharmacology Res & Perspec

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“…5,6 Brainderived neurotrophic factor (BDNF) is described as a neuronal-survival and growth-promoting gene also capable of exerting pleiotropic effects on the immune cells within the inflammatory lesions of MS patients. 7,8 Immunohistochemical studies, moreover, showed that BDNF, in the context of MS-related inflammatory reactions, is released not only by neurons but also by T cells, microglia, macrophages and reactive astrocytes. 9,10 Next, we focused on BDNF antisense RNA (BDNF-AS) which is identified to be a naturally conserved long noncoding RNA (lncRNA).…”

Section: Introductionmentioning

confidence: 99%

Expression Analysis of BDNF Gene and BDNF-AS Long Noncoding RNA in Whole Blood Samples of Multiple Sclerosis Patients: Not Always a Negative Correlation between Them

Gharzi

Gangi

Sayad

et al. 2019

IJAAI

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Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS), in which axonal damage is a deteriorative factor. Brain-Derived Neurotrophic Factor (BDNF) is described as a neuronal-survival gene, also capable of exerting pleiotropic effects on the immune cells. Here, we aimed to investigate expression levels of BDNF and its antisense RNA, BDNF-AS, in Iranian MS patients. Our case-control study was based on collecting 50 whole blood samples of relapsing-remitting MS patients and 50 healthy controls. Then, expression analysis of BDNF and BDNF-AS was performed by Real-time quantitative PCR. We found a strong and positive correlation between BDNF and BDNF-AS in MS patients. This is while no significant difference in BDNF and BDNF-AS expression levels was seen between MS patients and controls (p>0.05). A significant and strong positive correlation was found between the expression levels of BDNF-AS and BDNF (r=0.785, p<0.0001). Further, significant positive moderate correlations of BDNF and BDNF-AS with other lncRNAs (GSTT1-AS1 and IFNG-AS1) and genes (TNF and IFNG) were revealed (p<0.0001). Additionally, there was no correlation between the BDNF and BDNF-AS expressions and disease duration, age at onset, and Expanded Disability Status Scale of Kurtzke (EDSS) (p>0.05). BDNF and BDNF-AS expression levels revealed insignificant discrepancies in patients and controls. We found a strong and positive correlation between BDNF and BDNF-AS in MS patients, which is, based on previous studies, a quit novel finding and can be further discussed by future works to unravel its possible application in MS. We suggest evaluation of different leukocytes subsets separately along with large cohort studies comprising a higher number of individuals from different ages to unravel the effects of other possible aspects.

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“…A total of n = 4 mice were used per time point per group. As per our standard in house protocols [ 6 , 7 , 9 , 11 ], EAE mice were immunized subcutaneously (SQ) with 200 µg MOGp35–55 in 200 µL of Complete Freund’s adjuvant (CFA) at the lower/upper back at Day 0 (induction kits from Hooke Laboratories (Lawrence, MA 01843, USA) (Cat, EK-2110)). Animals received two intraperitoneal (IP) injections of pertussis toxin (PTX: List Biological Laboratories; #179B) (0.2 µg in 100 µL of PBS at Days 0 and 1) to open up the blood brain barrier and facilitate the entry of pathogenic T cells to the CNS.…”

Section: Methodsmentioning

confidence: 99%

“…For example, several studies have shown that fingolimod [ 25 ], the first approved oral drug for MS, glatiramer acetate [ 26 , 27 , 28 ] and laquinimod [ 29 , 30 ] exert their beneficial effect in treating relapsing remitting MS (RRMS) by increasing BDNF levels. In addition to these findings, we have also published evidence to support the role of BDNF via tropomyosin-related kinase receptors (TrkB) in SC myelin repair [ 11 ].…”

Section: Introductionmentioning

confidence: 97%

“…In addition, several of our publications have identified a common interactive signaling network among cytokines, chemokines and neurotrophins that regulate the myelin repair process [ 6 , 7 , 8 , 9 ]. We have identified several key biological targets in this pathway [ 5 , 7 , 8 , 9 , 10 , 11 ], However, we have now expanded this list of biological targets to include the upstream transcriptional repressor of BDNF known as methyl CpG binding protein 2 (MeCP2) [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Experimental Autoimmune Encephalomyelitis (EAE)-Induced Elevated Expression of the E1 Isoform of Methyl CpG Binding Protein 2 (MeCP2E1): Implications in Multiple Sclerosis (MS)-Induced Neurological Disability and Associated Myelin Damage

Ahmad

Zhou

Al-Taweel

et al. 2017

IJMS

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Multiple sclerosis (MS) is a chronic neurological disease characterized by the destruction of central nervous system (CNS) myelin. At present, there is no cure for MS due to the inability to repair damaged myelin. Although the neurotrophin brain derived neurotrophic factor (BDNF) has a beneficial role in myelin repair, these effects may be hampered by the over-expression of a transcriptional repressor isoform of methyl CpG binding protein 2 (MeCP2) called MeCP2E1. We hypothesize that following experimental autoimmune encephalomyelitis (EAE)-induced myelin damage, the immune system induction of the pathogenic MeCP2E1 isoform hampers the myelin repair process by repressing BDNF expression. Using an EAE model of MS, we identify the temporal gene and protein expression changes of MeCP2E1, MeCP2E2 and BDNF. The expression changes of these key biological targets were then correlated with the temporal changes in neurological disability scores (NDS) over the entire disease course. Our results indicate that MeCP2E1 mRNA levels are elevated in EAE animals relative to naïve control (NC) and active control (AC) animals during all time points of disease progression. Our results suggest that the EAE-induced elevations in MeCP2E1 expression contribute to the repressed BDNF production in the spinal cord (SC). The sub-optimal levels of BDNF result in sustained NDS and associated myelin damage throughout the entire disease course. Conversely, we observed no significant differences in the expression patterns displayed for the MeCP2E2 isoform amongst our experimental groups. However, our results demonstrate that baseline protein expression ratios between the MeCP2E1 versus MeCP2E2 isoforms in the SC are higher than those identified within the dorsal root ganglia (DRG). Thus, the DRG represents a more conducive environment than that of the SC for BDNF production and transport to the CNS to assist in myelin repair. Henceforth, the sub-optimal BDNF levels we report in the SC may arise from the elevated MeCP2E1 vs. MeCP2E2 ratio in the SC that creates a more hostile environment thereby preventing local BDNF production. At the level of transcript, we demonstrate that EAE-induces the pathological enhanced expression of MeCP2E1 that contributes to enhanced NDS during the entire disease course. Thus, the pathological induction of the MeCP2E1 isoform contributes to the disruption of the normal homeostatic signaling equilibrium network that exists between cytokines, neurotrophins and chemokines that regulate the myelin repair process by repressing BDNF. Our research suggests that the elevated ratio of MeCP2E1 relative to MeCP2E2 may be a useful diagnostic marker that clinicians can utilize to determine the degree of neurological disability with associated myelin damage. The elevated MeCP2E1 vs. MeCP2E2 ratios (E1/E2) in the SC prevent BDNF from reaching optimal levels required for myelin repair. Thus, the lower E1/E2 ratios in the DRG, allow the DRG to serve as a weak secondary compensatory mechanism for enhanced production and delivery of BD...

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Spinal Cord Brain Derived Neurotrophic Factor (BDNF) Responsive Cells in an Experimental Autoimmune Encephalomyelitis (EAE) Model of Multiple Sclerosis (MS): Implications in Myelin Repair

Cited by 6 publications

References 75 publications

Antiallodynic effects of alpha lipoic acid in an optimized RR‐EAE mouse model of MS‐neuropathic pain are accompanied by attenuation of upregulated BDNF‐TrkB‐ERK signaling in the dorsal horn of the spinal cord

Antiallodynic effects of alpha lipoic acid in an optimized RR‐EAE mouse model of MS‐neuropathic pain are accompanied by attenuation of upregulated BDNF‐TrkB‐ERK signaling in the dorsal horn of the spinal cord

Expression Analysis of BDNF Gene and BDNF-AS Long Noncoding RNA in Whole Blood Samples of Multiple Sclerosis Patients: Not Always a Negative Correlation between Them

Experimental Autoimmune Encephalomyelitis (EAE)-Induced Elevated Expression of the E1 Isoform of Methyl CpG Binding Protein 2 (MeCP2E1): Implications in Multiple Sclerosis (MS)-Induced Neurological Disability and Associated Myelin Damage

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