Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

Abstract Background: Pyridoxine (PDX; vitamin B 6 ), is an essential vitamin. PDX deficiency induces various symptoms, and when PDX is misused it acts as a neurotoxicant, inducing severe sensory neuropathy. Results: To assess the possibility of creating a reversible sensory neuropathy model using dogs, 150 mg/kg of PDX was injected subcutaneously into dogs for seven days and body weight measurements, postural reaction assessments, and electrophysiological recordings were obtained. In addition, the morphology of dorsal root ganglia (DRG) and changes in glial fibrillary acidic protein (GFAP) immunoreactive satellite glial cells and ionized calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia/macrophages were assessed at 1 day, 1 week, and 4 weeks after the last PDX treatment. During the administration period, body weight and proprioceptive losses occurred. One day after the last PDX treatment, electrophysiological recordings showed the absence of the H-reflex in the treated dogs. These phenomena persisted over the four post-treatment weeks, with the exception of body weight which recovered to the pre-treatment level. Staining (CV and HE) results revealed significant losses of large-sized neurons in the DRG at 1 day and 1 week after PDX treatment cessation, but the losses were recovered at 4 weeks post-treatment. The Iba-1 and GFAP immunohistochemistry results showed pronounced increases in reactive microglia/macrophage and satellite glial cell at 1 day and 1 week, respectively, after the last PDX treatment, and thereafter, immunoreactivity decreased with increasing time after PDX treatment. Conclusions: The results suggest that PDX-induced neuropathy is reversible in dogs; thus, dogs can be considered a good experimental model for research on neuropathy.

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Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

10.21203/rs.2.17162/v3 ◽

2020 ◽

Author(s):

Sumin Yun ◽

Woosuk Kim ◽

Min Soo Kang ◽

Tae Hyeong Kim ◽

Yoonhwan Kim ◽

...

Keyword(s):

Body Weight ◽

Dorsal Root Ganglia ◽

Calcium Binding ◽

Dorsal Root ◽

Sensory Neuropathy ◽

Post Treatment ◽

Treatment Level ◽

Reactive Microglia ◽

Satellite Glial Cells ◽

Electrophysiological Recordings

Abstract Background: Pyridoxine (PDX; vitamin B6), is an essential vitamin. PDX deficiency induces various symptoms, and when PDX is misused it acts as a neurotoxicant, inducing severe sensory neuropathy. Results: To assess the possibility of creating a reversible sensory neuropathy model using dogs, 150 mg/kg of PDX was injected subcutaneously into dogs for seven days and body weight measurements, postural reaction assessments, and electrophysiological recordings were obtained. In addition, the morphology of dorsal root ganglia (DRG) and changes in glial fibrillary acidic protein (GFAP) immunoreactive satellite glial cells and ionized calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia/macrophages were assessed at 1 day, 1 week, and 4 weeks after the last PDX treatment. During the administration period, body weight and proprioceptive losses occurred. One day after the last PDX treatment, electrophysiological recordings showed the absence of the H-reflex in the treated dogs. These phenomena persisted over the four post-treatment weeks, with the exception of body weight which recovered to the pre-treatment level. Staining (CV and HE) results revealed significant losses of large-sized neurons in the DRG at 1 day and 1 week after PDX treatment cessation, but the losses were recovered at 4 weeks post-treatment. The Iba-1 and GFAP immunohistochemistry results showed pronounced increases in reactive microglia/macrophage and satellite glial cell at 1 day and 1 week, respectively, after the last PDX treatment, and thereafter, immunoreactivity decreased with increasing time after PDX treatment. Conclusions: The results suggest that PDX-induced neuropathy is reversible in dogs; thus, dogs can be considered a good experimental model for research on neuropathy.

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Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

10.21203/rs.2.17162/v4 ◽

2020 ◽

Author(s):

Sumin Yun ◽

Woosuk Kim ◽

Min Soo Kang ◽

Tae Hyeong Kim ◽

Yoonhwan Kim ◽

...

Keyword(s):

Body Weight ◽

Dorsal Root Ganglia ◽

Calcium Binding ◽

Dorsal Root ◽

Sensory Neuropathy ◽

Post Treatment ◽

Treatment Level ◽

Reactive Microglia ◽

Satellite Glial Cells ◽

Electrophysiological Recordings

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Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

10.21203/rs.2.17162/v2 ◽

2020 ◽

Author(s):

Sumin Yun ◽

Woosuk Kim ◽

Min Soo Kang ◽

Tae Hyeong Kim ◽

Yoonhwan Kim ◽

...

Keyword(s):

Body Weight ◽

Glial Cells ◽

Dorsal Root Ganglia ◽

Calcium Binding ◽

Dorsal Root ◽

Sensory Neuropathy ◽

Significant Loss ◽

Reactive Microglia ◽

Satellite Glial Cells ◽

Electrophysiological Recordings

Abstract Background: Pyridoxine (PDX), vitamin B6, is an essential vitamin. PDX deficiency induces various symptoms and abuse of PDX supplement also acts as a neurotoxicant that induces severe sensory neuropathy. Results: To assess the possibility of reversible sensory neuropathy model using dogs, 150 mg/kg pyridoxine (PDX) was injected subcutaneously into dogs for seven days and body weight measurement, postural reaction assessments, and electrophysiological recordings were conducted. In addition, the morphology of dorsal root ganglia (DRG) and changes of glial fibrillary acidic protein (GFAP) immunoreactive satellite glial cells and ionized calcium-binding adapter molecule 1 (Iba-1) immunoreactive microglia/macrophages were observed at 0, 1 and 4 weeks after the last PDX treatment. During the administration period, body weight loss and proprioceptive loss occurred. After the treatments were completed, electrophysiological recordings showed that the H-reflex of the treated dogs had disappeared at week 0. These phenomena persisted for four weeks exceptional body weight. CV and HE staining revealed that neurons in DRG had significant loss of large-sized neurons 0 and 1 week, but these neurons were recovered 4 weeks. Iba-1 and GFAP immunohistochemistry showed that reactive microglia/macrophages and satellite glial cells were pronounced at 0 and 1 weeks after the last PDX treatment, respectively and thereafter decreased with time after PDX treatment, respectively.Conclusions: This result suggests that PDX-induced neuropathy model is reversible and can be a good experimental model for research on neuropathy in dogs.

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Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

10.21203/rs.2.17162/v1 ◽

2019 ◽

Author(s):

Sumin Yun ◽

Woosuk Kim ◽

Min Soo Kang ◽

Tae Hyeong Kim ◽

Yoonhwan Kim ◽

...

Keyword(s):

Weight Loss ◽

Body Weight ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Body Weight Loss ◽

Sensory Neuropathy ◽

Significant Loss ◽

Vitamin B ◽

Satellite Glial Cells ◽

Electrophysiological Recordings

Abstract Background: Pyridoxine (PDX), vitamin B 6 , is an essential vitamin. PDX deficiency induces various symptoms and abuse of PDX supplement also acts as a neurotoxicant that induces severe sensory neuropathy. Results: To construct a sensory neuropathy model in dogs, excess pyridoxine (PDX) was injected subcutaneously into dogs for seven days and dorsal root ganglia (DRG) were observed at 0, 1 and 4 weeks after the last PDX treatment. During the administration period, body weight loss and proprioceptive loss occurred. After the treatments were completed, electrophysiological recordings showed that the H-reflex of the treated dogs had disappeared at week 0. These phenomena persisted for four weeks exceptional body weight. CV and HE staining revealed that neurons in DRG had significant loss of large-sized neurons 0 weeks, but these neurons were recovered 4 weeks. Iba-1 and GFAP immunohistochemistry showed that reactive microgliosis and satellite glial cells were pronounced at 1 week. Conclusions: This result suggests that PDX-induced neuropathy model is reversible and can be a good experimental model for research on neuropathy in dogs.

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Morphological and electrophysiological changes in mouse dorsal root ganglia after partial colonic obstruction

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00028.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. G670-G678 ◽

Cited By ~ 36

Author(s):

Tian-Ying Huang ◽

Menachem Hanani

Keyword(s):

Glial Cells ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Neuronal Excitability ◽

Colonic Obstruction ◽

Resting Potential ◽

Dye Coupling ◽

Drg Neurons ◽

Satellite Glial Cells ◽

Colon Wall

There is evidence that sensitization of neurons in dorsal root ganglia (DRG) may contribute to pain induced by intestinal injury. We hypothesized that obstruction-induced pain is related to changes in DRG neurons and satellite glial cells (SGCs). In this study, partial colonic obstruction was induced by ligation. The neurons projecting to the colon were traced by an injection of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate into the colon wall. The electrophysiological properties of DRG neurons were determined using intracellular electrodes. Dye coupling was examined with an intracellular injection of Lucifer yellow (LY). Morphological changes in the colon and DRG were examined. Pain was assessed with von Frey hairs. Partial colonic obstruction caused the following changes. First, coupling between SGCs enveloping different neurons increased 18-fold when LY was injected into SGCs near neurons projecting to the colon. Second, neurons were not coupled to other neurons or SGCs. Third, the firing threshold of neurons projecting to the colon decreased by more than 40% ( P < 0.01), and the resting potential was more positive by 4–6 mV ( P < 0.05). Finally, the number of neurons displaying spontaneous spikes increased eightfold, and the number of neurons with subthreshold voltage oscillations increased over threefold. These changes are consistent with augmented neuronal excitability. The pain threshold to abdominal stimulation decreased by 70.2%. Inflammatory responses were found in the colon wall. We conclude that obstruction increased neuronal excitability, which is likely to be a major factor in the pain behavior observed. The augmented dye coupling between glial cells may contribute to the neuronal hyperexcitability.

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Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity.

Journal of Clinical Oncology ◽

10.1200/jco.1992.10.5.795 ◽

1992 ◽

Vol 10 (5) ◽

pp. 795-803 ◽

Cited By ~ 241

Author(s):

R W Gregg ◽

J M Molepo ◽

V J Monpetit ◽

N Z Mikael ◽

D Redmond ◽

...

Keyword(s):

Dorsal Root Ganglia ◽

Cumulative Dose ◽

Dorsal Root ◽

Sensory Neuropathy ◽

Neural Tissue ◽

Neural Structure ◽

Neural Tissues ◽

Index Of Exposure ◽

Platinum Accumulation ◽

The Relationship

PURPOSE To identify the major sites of platinum accumulation within neural tissues after treatment with cisplatin and to determine the relationship between cumulative dosage, time, and the development of histopathological and clinical neurotoxicity. PATIENTS AND METHODS Twenty-one patients treated antemortem with cisplatin had neural tissue harvested at autopsy. Neural tissues were assayed for platinum and examined for histopathologic evidence of neurotoxicity. The relationship between histopathologic neurotoxicity and various pharmacologic parameters was analyzed. RESULTS Tissue platinum levels were found to be highest in the dorsal root ganglia and lowest in tissue protected by the blood-brain barrier. For peripheral nerve, dorsal root, and dorsal root ganglia, a linear relationship was observed between platinum levels and cumulative dose. Platinum levels in neural tissue were not observed to decrease with time. Histopathologic toxicity closely matched an index of exposure to platinum (cumulative dose and log of time). Clinical and histopathologic neurotoxicity was found to occur with higher accumulations of platinum, with the highest levels found in patients with clinical evidence of neurotoxicity. CONCLUSIONS The dorsal root ganglia was the most vulnerable neural structure. This is consistent with the clinical presentation of sensory neuropathy in cisplatin neurotoxicity. Central structures of the spinal cord and brain were protected from platinum accumulation. The increasing histopathologic toxicity, with an index of exposure to platinum, suggests that it is retained indefinitely in an actively neurotoxic form. The pharmacologic parameters examined correlate with the development of and are consistent with the clinical and laboratory features of cisplatin neurotoxicity.

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Purinergic signaling between neurons and satellite glial cells of mouse dorsal root ganglia modulates neuronal excitability in vivo

Pain ◽

10.1097/j.pain.0000000000002556 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Zhiyong Chen ◽

Qian Huang ◽

Xiaodan Song ◽

Neil C. Ford ◽

Chi Zhang ◽

...

Keyword(s):

Glial Cells ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Neuronal Excitability ◽

Purinergic Signaling ◽

Satellite Glial Cells

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RNA-Binding Proteins HuB, HuC, and HuD are Distinctly Regulated in Dorsal Root Ganglia Neurons from STZ-Sensitive Compared to STZ-Resistant Diabetic Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20081965 ◽

2019 ◽

Vol 20 (8) ◽

pp. 1965 ◽

Cited By ~ 1

Author(s):

Cosmin Cătălin Mustăciosu ◽

Adela Banciu ◽

Călin Mircea Rusu ◽

Daniel Dumitru Banciu ◽

Diana Savu ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Sensory Neurons ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Transcriptional Control ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Diabetic Mice

The neuron-specific Elav-like Hu RNA-binding proteins were described to play an important role in neuronal differentiation and plasticity by ensuring the post-transcriptional control of RNAs encoding for various proteins. Although Elav-like Hu proteins alterations were reported in diabetes or neuropathy, little is known about the regulation of neuron-specific Elav-like Hu RNA-binding proteins in sensory neurons of dorsal root ganglia (DRG) due to the diabetic condition. The goal of our study was to analyze the gene and protein expression of HuB, HuC, and HuD in DRG sensory neurons in diabetes. The diabetic condition was induced in CD-1 adult male mice with single-intraperitoneal injection of streptozotocin (STZ, 150 mg/kg), and 8-weeks (advanced diabetes) after induction was quantified the Elav-like proteins expression. Based on the glycemia values, we identified two types of responses to STZ, and mice were classified in STZ-resistant (diabetic resistant, glycemia < 260 mg/dL) and STZ-sensitive (diabetic, glycemia > 260 mg/dL). Body weight measurements indicated that 8-weeks after STZ-induction of diabetes, control mice have a higher increase in body weight compared to the diabetic and diabetic resistant mice. Moreover, after 8-weeks, diabetic mice (19.52 ± 3.52 s) have longer paw withdrawal latencies in the hot-plate test than diabetic resistant (11.36 ± 1.92 s) and control (11.03 ± 1.97 s) mice, that correlates with the installation of warm hypoalgesia due to the diabetic condition. Further on, we evidenced the decrease of Elav-like gene expression in DRG neurons of diabetic mice (Elavl2, 0.68 ± 0.05 fold; Elavl3, 0.65 ± 0.01 fold; Elavl4, 0.53 ± 0.07 fold) and diabetic resistant mice (Ealvl2, 0.56 ± 0.07 fold; Elavl3, 0.32 ± 0.09 fold) compared to control mice. Interestingly, Elav-like genes have a more accentuated downregulation in diabetic resistant than in diabetic mice, although hypoalgesia was evidenced only in diabetic mice. The Elav-like gene expression changes do not always correlate with the Hu protein expression changes. To detail, HuB is upregulated and HuD is downregulated in diabetic mice, while HuB, HuC, and HuD are downregulated in diabetic resistant mice compared to control mice. To resume, we demonstrated HuD downregulation and HuB upregulation in DRG sensory neurons induced by diabetes, which might be correlated with altered post-transcriptional control of RNAs involved in the regulation of thermal hypoalgesia condition caused by the advanced diabetic neuropathy.

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