Involvement of TrkB- and p75NTR-signaling pathways in two contrasting forms of long-lasting synaptic plasticity

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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“…; Sakuragi et al. ). As pERK is regarded as a marker of central sensitization in peripheral neuropathic pain conditions (Zhuang et al.…”

Section: Discussionmentioning

confidence: 96%

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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“…At the same time, plasmin activity in the brain is typically dependent on tPA . Thus, tPA/PAI‐1 system represent an important regulator of extracellular BDNF/pro‐BDNF ratio …”

Section: Plasminogen Activation System and The Regulation Of Bdnf Matmentioning

confidence: 99%

“…Expression of pro‐BDNF may also elicit additional effects, such as growth cone retraction, axonal pruning, LTD induction, and synaptic elimination of neuromuscular junctions . These effects contrast with those elicited by BDNF, leading to the “yin‐yang” neurotrophin hypothesis in which mature BDNF and pro‐BDNF exhibit opposing functions mediated by the activations of their respective receptors, TrkB and p75 …”

Section: Role Of Bdnf and Pro‐bdnf In The Cnsmentioning

confidence: 99%

“…59 Thus, tPA/PAI-1 system represent an important regulator of extracellular BDNF/pro-BDNF ratio. 60 It has been shown that exogenous tPA administration increases hippocampal BDNF levels 61 and the conversion of pro-BDNF to BDNF by plasmin is essential for LTP late-phases. 62,63 In addition, a defective tPA/plasmin/PAI-1-mediated BDNF maturation has been claimed to be involved in the manifestation of some brain pathologies, such as substance abuse and addiction, 64,65 depression, 66 and stress.…”

Section: Pl a S Minog En Ac Tivati On Sys Tem And The Reg Ul Ati Onmentioning

confidence: 99%

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Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease: Consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications

et al. 2018

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Summary Soluble oligomeric forms of amyloid beta (Aβ) play an important role in causing the cognitive deficits in Alzheimer’s disease (AD) by targeting and disrupting synaptic pathways. Thus, the present research is directed toward identifying the neuronal pathways targeted by soluble forms and, accordingly, develops alternative therapeutic strategies. The neurotrophin brain‐derived neurotrophic factor (BDNF) is synthesized as a precursor (pro‐BDNF) which is cleaved extracellularly by plasmin to release the mature form. The conversion from pro‐BDNF to BDNF is an important process that regulates neuronal activity and memory processes. Plasmin‐dependent maturation of BDNF in the brain is regulated by plasminogen activator inhibitor‐1 (PAI‐1), the natural inhibitor of tissue‐type plasminogen activator (tPA). Therefore, tPA/PAI‐1 system represents an important regulator of extracellular BDNF/pro‐BDNF ratio. In this review, we summarize the data on the components of the plasminogen activation system and on BDNF in AD. Moreover, we will hypothesize a possible pathogenic mechanism caused by soluble Aβ forms based on the effects on tPA/PAI‐1 system and on the consequence of an altered conversion from pro‐BDNF to the mature BDNF in the brain of AD patients. Translation into clinic may include a better characterization of the disease stage and future direction on therapeutic targets.

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“…This study reveals a novel mechanism of cholesterol oxidation-induced alteration in raft dynamics leading to dominance of p75 receptor-mediated death signal in hippocampal neurons during chronic hypoxia. Previous studies report diametrically opposite function of mature BDNF and pro-BDNF by activating their preferred cognate receptors that is, either Trkb or p75 (Sakuragi et al 2013). Our study, however, reveals the receptor subtype composition in the synaptic membrane to be the determining factor governing the physiological role of different BDNF isoforms.…”

Section: Discussionmentioning

confidence: 98%

Hypoxia‐mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus

Sharma

Barhwal

Biswal

et al. 2018

Journal of Neurochemistry

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Brain‐derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF‐mediated pro‐death signalling in hypoxia, however, still remain an enigma. This study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Adult Sprague–Dawley rats were exposed to global hypobaric hypoxia simulating an altitude of 7620 m at standard temperature and humidity. Chronic hypoxic exposure for 7 days resulted in higher expression of pro‐BDNF and alteration in N‐linked glycosylation in hippocampus along with increased expression of endoplasmic reticulum stress markers viz., glucose‐regulated protein (Grp78), calnexin and changes in the endoplasmic reticulum morphology. Our findings reveal enriched expression of p75NTR in lipid rafts and higher expression of tyrosine receptor kinase β (Trkβ) in non‐raft regions following hypoxic exposure. Further investigations on membrane properties revealed decline in membrane fluidity along with increased cholesterol oxidation resulting in reduced translocation of Trkβ from non‐raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkβ from non‐raft to raft regions and promoted neuronal survival. Hence, our findings suggest a novel mechanism of cholesterol oxidation‐induced alteration in raft dynamics which is promotes p75 receptor‐mediated death signalling in hippocampal neurons during chronic hypoxia.

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Involvement of TrkB- and p75NTR-signaling pathways in two contrasting forms of long-lasting synaptic plasticity

Cited by 47 publications

References 45 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

Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease: Consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications

Hypoxia‐mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus

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