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

1992 ◽  
Vol 10 (5) ◽  
pp. 795-803 ◽  
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.

scholarly journals Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

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.

scholarly journals Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

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 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.

scholarly journals Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

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 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.

scholarly journals Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

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.

Antibodies to dorsal root ganglia and olfactory cells in a patient with chronic sensory neuropathy and anosmia

2004 ◽  
Vol 221 (1-2) ◽  
pp. 105-108 ◽  
Author(s):  
Simona Gambelli ◽  
Federica Ginanneschi ◽  
Alessandro Malandrini ◽  
Silvia Palmeri ◽  
Gianna Berti ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Sensory Neuropathy ◽  
Olfactory Cells

scholarly journals Neuropathological changes in dorsal root ganglia induced by pyridoxine in dogs

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.

Metformin reduces c-Fos and ATF3 expression in the dorsal root ganglia and protects against oxaliplatin-induced peripheral sensory neuropathy in mice

2019 ◽  
Vol 709 ◽  
pp. 134378 ◽  
Author(s):  
Anamaria Falcão Pereira ◽  
Lus Mário Silva Pereira ◽  
Cristiane Maria Pereira Silva ◽  
Bruno Wesley Freitas Alves ◽  
Jéssica Sales Barbosa ◽  
...  
Keyword(s):  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Sensory Neuropathy ◽  
Peripheral Sensory Neuropathy ◽  
Peripheral Sensory ◽  
Atf3 Expression

scholarly journals Pathomechanisms of Paclitaxel-Induced Peripheral Neuropathy

Toxics ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 229
Author(s):  
Ines Klein ◽  
Helmar C. Lehmann
Keyword(s):  
Nervous System ◽  
Peripheral Neuropathy ◽  
Cancer Patients ◽  
Peripheral Nervous System ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Sensory Neuropathy ◽  
Pain Sensation ◽  
Microtubule Stabilization ◽  
Hands And Feet

Peripheral neuropathy is one of the most common side effects of chemotherapy, affecting up to 60% of all cancer patients receiving chemotherapy. Moreover, paclitaxel induces neuropathy in up to 97% of all gynecological and urological cancer patients. In cancer cells, paclitaxel induces cell death via microtubule stabilization interrupting cell mitosis. However, paclitaxel also affects cells of the central and peripheral nervous system. The main symptoms are pain and numbness in hands and feet due to paclitaxel accumulation in the dorsal root ganglia. This review describes in detail the pathomechanisms of paclitaxel in the peripheral nervous system. Symptoms occur due to a length-dependent axonal sensory neuropathy, where axons are symmetrically damaged and die back. Due to microtubule stabilization, axonal transport is disrupted, leading to ATP undersupply and oxidative stress. Moreover, mitochondria morphology is altered during paclitaxel treatment. A key player in pain sensation and axonal damage is the paclitaxel-induced inflammation in the spinal cord as well as the dorsal root ganglia. An increased expression of chemokines and cytokines such as IL-1β, IL-8, and TNF-α, but also CXCR4, RAGE, CXCL1, CXCL12, CX3CL1, and C3 promote glial activation and accumulation, and pain sensation. These findings are further elucidated in this review.

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