ABSTRACT
Nerve agents are used in civil wars and terrorist attacks, posing a threat to public safety. Acute exposure to nerve agents such as soman (GD) causes serious brain damage, leading to death due to intense seizures induced by acetylcholinesterase inhibition and neuronal injury resulting from increased excitatory amino-acid levels and neuroinflammation. However, data on the anticonvulsant and neuroprotective efficacies of currently-used countermeasures are limited. Here, we evaluated the potential effects of transient receptor vanilloid 4 (TRPV4) in the treatment of soman-induced status epilepticus (SE) and secondary brain injury. We demonstrated that TRPV4 expression was markedly up-regulated in rat hippocampus after soman-induced seizures. Administration of the TRPV4 antagonist GSK2193874 prior to soman exposure significantly decreased the mortality rate in rats and reduced SE intensity. TRPV4-knockout mice also showed lower incidence of seizures and higher survival rates than wild-type mice following soman exposure. Further in vivo and in vitro experiments demonstrated that blocking TRPV4 prevented NMDA receptor-mediated glutamate excitotoxicity. The protein levels of the NLRP3 inflammasome complex and its downstream cytokines IL-1β and IL-18 increased in soman-exposed rat hippocampus. However, TRPV4 inhibition or deletion markedly reversed the activation of the NLRP3 inflammasome pathway. In conclusion, our study suggests that the blockade of TRPV4 protects against soman exposure and reduces brain injury following SE by decreasing NMDA receptor-mediated excitotoxicity and NLRP3-mediated neuroinflammation. To our knowledge, this is the first study regarding the “dual-switch” function of TRPV4 in the treatment of soman intoxication.
ABSTRACT
OBJECTIVE@#To investigate the efficacy of prussian blue (PB) or its combination with hemoperfusion (HP) in the treatment of acute thallium poisoning.@*METHODS@#Forty-seven patients with acute thallium poisoning with complete data hospitalized in the 307th Hospital of PLA from September 2002 to December 2017 were enrolled, and they were divided into mild poisoning group (blood thallium < 150 μg/L, urinary thallium < 1 000 μg/L) and moderate-severe poisoning group (blood thallium ≥ 150 μg/L, urinary thallium ≥ 1 000 μg/L) according to the toxic degrees. All patients were given symptomatic supportive treatments such as potassium supplementation, catharsis, vital organ protections, neurotrophic drugs, and circulation support. The mild poisoning patients were given PB with an oral dose of 250 mg×kg-1×d-1, while moderate-severe poisoning patients were given PB combined HP continued 2-4 hours each time. The PB dose or frequency of HP application was adjusted according to the monitoring results of blood and urine thallium. Data of gender, age, pain grading (numeric rating scale NRS), clinical manifestations, blood and urine thallium before and after treatment, length of hospitalization and prognosis were collected.@*RESULTS@#Of the 47 patients, patients with incomplete blood and urine test results, and used non-single HP treatment such as plasmapheresis and hemodialysis for treatment were excluded, and a total of 29 patients were enrolled in the analysis. (1) Among 29 patients, there were 20 males and 9 females, median age of 40.0 (34.0, 49.0) years old; the main clinical manifestations were nervous system and alopecia, some patients had digestive system symptoms. There were 13 patients (44.8%) in the mild poisoning group with painless (grade 0) or mild pain (grade 1-3) with mild clinical symptoms, the length of hospitalization was 17.0 (14.2, 21.5) days. There were 16 patients (55.2%) in the moderate-severe poisoning group with moderate pain (grade 4-6) or severe pain (grade 7-10) with severe clinical symptoms, the length of hospitalization was 24.0 (18.0, 29.0) days. (2) After treatment, the thallium concentrations in blood and urine in the mild poisoning group were significantly lower than those before treatment [μg/L: blood thallium was 0.80 (0, 8.83) vs. 60.00 (40.00, 120.00), urine thallium was 11.30 (0, 70.10) vs. 370.00 (168.30, 610.00), both P < 0.01], the thallium concentrations in blood and urine in the moderate-severe poisoning group were also significantly lower than those before treatment [μg/L: blood thallium was 6.95 (0, 50.50) vs. 614.50 (245.00, 922.00), urinary thallium was 20.70 (1.95, 283.00) vs. 5 434.00 (4 077.20, 10 273.00), both P < 0.01]. None of the 29 patients died, and their clinical symptoms were improved significantly. All the 27 patients had good prognosis without sequela in half a year follow-up, and 2 patients with severe acute thallium poisoning suffered from nervous system injury.@*CONCLUSIONS@#In the acute thallium poisoning patients, on the basis of general treatment, additional PB in mild poisoning group and PB combined with HP in moderate-severe poisoning group can obtain satisfactory curative effects.
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Ferrocyanides , Heavy Metal Poisoning , Hemoperfusion , Thallium/poisoningABSTRACT
Objective@#To investigate the efficacy of prussian blue (PB) or its combination with hemoperfusion (HP) in the treatment of acute thallium poisoning.@*Methods@#Forty-seven patients with acute thallium poisoning with complete data hospitalized in the 307th Hospital of PLA from September 2002 to December 2017 were enrolled, and they were divided into mild poisoning group (blood thallium < 150 μg/L, urinary thallium < 1 000 μg/L) and moderate-severe poisoning group (blood thallium ≥ 150 μg/L, urinary thallium ≥ 1 000 μg/L) according to the toxic degrees. All patients were given symptomatic supportive treatments such as potassium supplementation, catharsis, vital organ protections, neurotrophic drugs, and circulation support. The mild poisoning patients were given PB with an oral dose of 250 mg·kg-1·d-1, while moderate-severe poisoning patients were given PB combined HP continued 2-4 hours each time. The PB dose or frequency of HP application was adjusted according to the monitoring results of blood and urine thallium. Data of gender, age, pain grading (numeric rating scale NRS), clinical manifestations, blood and urine thallium before and after treatment, length of hospitalization and prognosis were collected.@*Results@#Of the 47 patients, patients with incomplete blood and urine test results, and used non-single HP treatment such as plasmapheresis and hemodialysis for treatment were excluded, and a total of 29 patients were enrolled in the analysis. ①Among 29 patients, there were 20 males and 9 females, median age of 40.0 (34.0, 49.0) years old; the main clinical manifestations were nervous system and alopecia, some patients had digestive system symptoms. There were 13 patients (44.8%) in the mild poisoning group with painless (grade 0) or mild pain (grade 1-3) with mild clinical symptoms, the length of hospitalization was 17.0 (14.2, 21.5) days. There were 16 patients (55.2%) in the moderate-severe poisoning group with moderate pain (grade 4-6) or severe pain (grade 7-10) with severe clinical symptoms, the length of hospitalization was 24.0 (18.0, 29.0) days. ② After treatment, the thallium concentrations in blood and urine in the mild poisoning group were significantly lower than those before treatment [μg/L: blood thallium was 0.80 (0, 8.83) vs. 60.00 (40.00, 120.00), urine thallium was 11.30 (0, 70.10) vs. 370.00 (168.30, 610.00), both P < 0.01], the thallium concentrations in blood and urine in the moderate-severe poisoning group were also significantly lower than those before treatment [μg/L: blood thallium was 6.95 (0, 50.50) vs. 614.50 (245.00, 922.00), urinary thallium was 20.70 (1.95, 283.00) vs. 5 434.00 (4 077.20, 10 273.00), both P < 0.01]. None of the 29 patients died, and their clinical symptoms were improved significantly. All the 27 patients had good prognosis without sequela in half a year follow-up, and 2 patients with severe acute thallium poisoning suffered from nervous system injury.@*Conclusion@#In the acute thallium poisoning patients, on the basis of general treatment, additional PB in mild poisoning group and PB combined with HP in moderate-severe poisoning group can obtain satisfactory curative effects.