Post-stroke administration of the p75 neurotrophin receptor modulator, LM11A-31, attenuates chronic changes in brain metabolism, increases neurotransmitter levels, and improves recovery

AbstractBrain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of post-stroke depression (PSD). However, the precise function and potential mechanism of proBDNF, the precursor form of BDNF, are unknown. In our study, a PSD-like model was established by treating neuronal cells with oxygen-glucose deprivation and corticosterone. We found that the protein proBDNF levels were significantly higher in the cortex and hippocampus in the PSD group than in the control group, suggesting that proBDNF plays a role in the pathophysiology of PSD. Furthermore, we re-established the PSD-like cell model using recombinant p75 neurotrophin receptor (p75NTR) or silencing c-Jun N-terminal kinase (JNK), and found that the PSD-induced upregulation of proBDNF was inhibited by recombinant p75NTR and JNK silencing (siJNK), and increased cellular apoptosis. Moreover, the application of recombinant p75NTR and siJNK in the PSD-like cell model significantly reversed the expression of apoptosis-related and depression-related proteins and decreased cellular apoptosis. Our findings suggest that proBDNF is involved in neural plasticity in PSD in vitro. The RhoA-JNK signaling pathway is activated after proBDNF binds to the p75NTR receptor, followed by the expression of apoptosis-related proteins (PSD95, synaptophysin, and P-cofilin), which contribute to PSD progression. The mechanism might involve the promotion of cellular apoptosis and the inhibition of nerve synapses regeneration by proBDNF.

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Post-stroke administration of the p75 neurotrophin receptor modulator, LM11A-31, attenuates chronic changes in brain metabolism, increases neurotransmitter levels, and improves recovery

10.1101/2021.04.30.442181 ◽

2021 ◽

Author(s):

Thuy-Vi V. Nguyen ◽

Rachael H. Crumpacker ◽

Kylie E. Calderon ◽

Frankie G. Garcia ◽

Jacob C. Zbesko ◽

...

Keyword(s):

Small Molecule ◽

Cognitive Abilities ◽

Immune Cell ◽

Principal Component ◽

Stroke Recovery ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Ipsilateral Hemisphere ◽

Chronic Inflammatory Response ◽

Post Stroke

ABSTRACTThe aim of this study was to test whether post-stroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle treated mice by principal component analysis, and had higher levels of glutamate, serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks following stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31 treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31 treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nesting test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor for preserving neuronal health and function during stroke recovery.SIGNIFICANCE STATEMENTThe findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer’s disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

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Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury

Journal of Sexual Medicine ◽

10.1016/j.jsxm.2020.10.015 ◽

2021 ◽

Vol 18 (1) ◽

pp. 17-28

Author(s):

Guo Nan Yin ◽

Jiyeon Ock ◽

Anita Limanjaya ◽

Nguyen Naht Minh ◽

Soon-Sun Hong ◽

...

Keyword(s):

Mouse Model ◽

Oral Administration ◽

Nerve Injury ◽

Erectile Function ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Cavernous Nerve ◽

Receptor Modulator ◽

Cavernous Nerve Injury

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Faculty Opinions recommendation of NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1001155.17064 ◽

2001 ◽

Author(s):

Chris Henderson

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Nerve Growth

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Faculty Opinions recommendation of Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005975.73013 ◽

2002 ◽

Author(s):

Guy Laurent

Keyword(s):

Synergistic Effect ◽

Inflammatory Cytokines ◽

Beta Amyloid ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Amyloid Peptides

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The Effects of P75NTR on Learning Memory Mediated by Hippocampal Apoptosis and Synaptic Plasticity

Current Pharmaceutical Design ◽

10.2174/1381612826666200916145142 ◽

2020 ◽

Vol 26 ◽

Author(s):

Jun-Jie Tang ◽

Shuang Feng ◽

Xing-Dong Chen ◽

Hua Huang ◽

Min Mao ◽

...

Keyword(s):

Synaptic Plasticity ◽

Learning And Memory ◽

Neurological Diseases ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Negative Effects ◽

Apoptotic Effect ◽

New Ideas ◽

The Relationship

: Neurological diseases bring great mental and physical torture to the patients, and have long-term and sustained negative effects on families and society. The attention to neurological diseases is increasing, and the improvement of the material level is accompanied by an increase in the demand for mental level. The p75 neurotrophin receptor (p75NTR) is a low-affinity neurotrophin receptor and involved in diverse and pleiotropic effects in the developmental and adult central nervous system (CNS). Since neurological diseases are usually accompanied by the regression of memory, the pathogenesis of p75NTR also activates and inhibits other signaling pathways, which has a serious impact on the learning and memory of patients. The results of studies shown that p75NTR is associated with LTP/LTD-induced synaptic enhancement and inhibition, suggest that p75NTR may be involved in the progression of synaptic plasticity. And its pro-apoptotic effect is associated with activation of proBDNF and inhibition of proNGF, and TrkA/p75NTR imbalance leads to pro-survival or pro-apoptotic phenomena. It can be inferred that p75NTR mediates apoptosis in the hippocampus and amygdale, which may affect learning and memory behavior. This article mainly discusses the relationship between p75NTR and learning memory and associated mechanisms, which may provide some new ideas for the treatment of neurological diseases.

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Acceleration of TAA-Induced Liver Fibrosis by Stress Exposure Is Associated with Upregulation of Nerve Growth Factor and Glycopattern Deviations

International Journal of Molecular Sciences ◽

10.3390/ijms22105055 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5055

Author(s):

Catalina Atorrasagasti ◽

Flavia Piccioni ◽

Sophia Borowski ◽

Irene Tirado-González ◽

Nancy Freitag ◽

...

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Liver Fibrosis ◽

Signaling Pathway ◽

Liver Damage ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Nerve Growth ◽

Fibrotic Process ◽

Ngf Signaling

Liver fibrosis results from many chronic injuries and may often progress to cirrhosis and hepatocellular carcinoma (HCC). In fact, up to 90% of HCC arise in a cirrhotic liver. Conversely, stress is implicated in liver damage, worsening disease outcome. Hence, stress could play a role in disrupting liver homeostasis, a concept that has not been fully explored. Here, in a murine model of TAA-induced liver fibrosis we identified nerve growth factor (NGF) to be a crucial regulator of the stress-induced fibrogenesis signaling pathway as it activates its receptor p75 neurotrophin receptor (p75NTR), increasing liver damage. Additionally, blocking the NGF decreased liver fibrosis whereas treatment with recombinant NGF accelerated the fibrotic process to a similar extent than stress challenge. We further show that the fibrogenesis induced by stress is characterized by specific changes in the hepatoglycocode (increased β1,6GlcNAc-branched complex N-glycans and decreased core 1 O-glycans expression) which are also observed in patients with advanced fibrosis compared to patients with a low level of fibrosis. Our study facilitates an understanding of stress-induced liver injury and identify NGF signaling pathway in early stages of the disease, which contributes to the established fibrogenesis.

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Cell non-autonomous requirement of p75 in the development of geniculate oral sensory neurons

Scientific Reports ◽

10.1038/s41598-020-78816-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tao Tang ◽

Christopher R. Donnelly ◽

Amol A. Shah ◽

Robert M. Bradley ◽

Charlotte M. Mistretta ◽

...

Keyword(s):

Sensory Neurons ◽

Significant Loss ◽

Taste Buds ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Chorda Tympani ◽

Chorda Tympani Nerve ◽

Tactile Stimuli ◽

Oral Sensory ◽

Nerve Recordings

AbstractDuring development of the peripheral taste system, oral sensory neurons of the geniculate ganglion project via the chorda tympani nerve to innervate taste buds in fungiform papillae. Germline deletion of the p75 neurotrophin receptor causes dramatic axon guidance and branching deficits, leading to a loss of geniculate neurons. To determine whether the developmental functions of p75 in geniculate neurons are cell autonomous, we deleted p75 specifically in Phox2b + oral sensory neurons (Phox2b-Cre; p75fx/fx) or in neural crest-derived cells (P0-Cre; p75fx/fx) and examined geniculate neuron development. In germline p75−/− mice half of all geniculate neurons were lost. The proportion of Phox2b + neurons, as compared to Phox2b-pinna-projecting neurons, was not altered, indicating that both populations were affected similarly. Chorda tympani nerve recordings demonstrated that p75−/− mice exhibit profound deficits in responses to taste and tactile stimuli. In contrast to p75−/− mice, there was no loss of geniculate neurons in either Phox2b-Cre; p75fx/fx or P0-Cre; p75fx/fx mice. Electrophysiological analyses demonstrated that Phox2b-Cre; p75fx/fx mice had normal taste and oral tactile responses. There was a modest but significant loss of fungiform taste buds in Phox2b-Cre; p75fx/fx mice, although there was not a loss of chemosensory innervation of the remaining fungiform taste buds. Overall, these data suggest that the developmental functions of p75 are largely cell non-autonomous and require p75 expression in other cell types of the chorda tympani circuit.

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