Nonsteroidal anti-inflammatory drug (ketoprofen) delivery differentially impacts phrenic long-term facilitation in rats with motor neuron death induced by intrapleural CTB-SAP injections

2021 ◽  
pp. 113892
Author(s):  
Lauren F. Borkowski ◽  
Amy N. Keilholz ◽  
Catherine L. Smith ◽  
Kaylie A. Canda ◽  
Nicole L. Nichols
Keyword(s):  
Motor Neuron ◽  
Neuron Death ◽  
Inflammatory Drug ◽  
Motor Neuron Death ◽  
Anti Inflammatory ◽  
Long Term Facilitation

Divergent receptor utilization is necessary for phrenic long-term facilitation over the course of motor neuron loss following CTB-SAP intrapleural injections

2021 ◽  
Author(s):  
Lauren F. Borkowski ◽  
Catherine L. Smith ◽  
Amy N. Keilholz ◽  
Nicole L. Nichols
Keyword(s):  
Motor Neuron ◽  
Receptor Antagonist ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Male Rats ◽  
Neuron Death ◽  
Receptor Inhibition ◽  
Motor Neuron Death ◽  
Long Term Facilitation

Intrapleural injection of cholera toxin B conjugated to saporin (CTB-SAP) mimics respiratory motor neuron death and respiratory deficits observed in rat models of neuromuscular diseases. 7d CTB-SAP rats elicit enhanced phrenic long-term facilitation (pLTF) primarily through TrkB and PI3K/Akt-dependent mechanisms (i.e., Gs-pathway, which can be initiated by adenosine 2A (A2A) receptors in naïve rats), while 28d CTB-SAP rats elicit moderate pLTF though BDNF and MEK/ERK-dependent mechanisms (i.e., Gq-pathway, which is typically initiated by serotonin (5-HT) receptors in naïve rats). Here, we tested the hypothesis that pLTF following CTB-SAP is: 1) A2A receptor-dependent at 7d; and 2) 5-HT receptor-dependent at 28d. Adult Sprague Dawley male rats were anesthetized, paralyzed, ventilated, and were exposed to acute intermittent hypoxia (AIH; 3, 5 min bouts of 10.5% O2) following bilateral, intrapleural injections at 7d and 28d of: 1) CTB-SAP (25 μg), or 2) un-conjugated CTB and SAP (control). Intrathecal C4 delivery included either the: 1) A2A receptor antagonist (MSX-3; 10 μM; 12 μl); or 2) 5-HT receptor antagonist (methysergide; 20 mM; 15 μl). pLTF was abolished with A2A receptor inhibition in 7d, not 28d, CTB-SAP rats vs. controls (p<0.05), while pLTF was abolished following 5-HT receptor inhibition in 28d, not 7d, CTB-SAP rats vs. controls (p<0.05). Additionally, 5-HT2A receptor expression was unchanged in CTB-SAP rats vs. controls, while 5-HT2B receptor expression was decreased in CTB-SAP rats vs. controls (p<0.05). This study furthers our understanding of the contribution of differential receptor activation to pLTF and its implications for breathing following respiratory motor neuron death.

scholarly journals Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism

2016 ◽  
Vol 113 (42) ◽  
pp. E6496-E6505 ◽  
Author(s):  
Laura Ferraiuolo ◽  
Kathrin Meyer ◽  
Thomas W. Sherwood ◽  
Jonathan Vick ◽  
Shibi Likhite ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Lactate Production ◽  
Chromosome 9 ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Repeat Expansions ◽  
Human Oligodendrocytes ◽  
Lateral Sclerosis ◽  
Dependent Mechanism

Oligodendrocytes have recently been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). Here we show that, in vitro, mutant superoxide dismutase 1 (SOD1) mouse oligodendrocytes induce WT motor neuron (MN) hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls and patients with sporadic and familial ALS, using two different reprogramming methods. All ALS oligodendrocyte lines induced MN death through conditioned medium (CM) and in coculture. CM-mediated MN death was associated with decreased lactate production and release, whereas toxicity in coculture was lactate-independent, demonstrating that MN survival is mediated not only by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in MN rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, whereas it was ineffective in differentiated oligodendrocytes. In fact, early SOD1 knockdown rescued lactate impairment and cell toxicity in all lines tested, with the exclusion of samples carrying chromosome 9 ORF 72 (C9orf72) repeat expansions. These did not respond to SOD1 knockdown nor did they show lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type, some damage might be irreversible. In addition, we demonstrate that patients with C9ORF72 represent an independent patient group that might not respond to the same treatment.

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