Cyanide-induced chemical hypoxia is responsible for pronounced oxidative damage in the central nervous system. The disruption of mitochondrial oxidative metabolism has been associated with upregulation of uncoupling proteins (UCPs). The present study addresses the dose- and time-dependent effect of sub-acute cyanide exposure on various non-enzymatic and enzymatic oxidative stress markers and their correlation with inducible-nitric oxide synthase (iNOS) and uncoupling protein-2 (UCP-2) expression. Animals received (oral) triple distilled water (vehicle control), 0.25 LD50 potassium cyanide (KCN) or 0.50 LD50 KCN daily for 21 d. Animals were sacrificed on 7, 14 and 21 d post-exposure to measure serum cyanide and nitrite, and brain malondialdehyde (MDA), reduced glutathione (GSH), glutathione disulfide (GSSG), cytochrome c oxidase (CCO), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CA) levels, together with iNOS and UCP-2 expression, and DNA damage. The study revealed that a dose- and time-dependent increase in cyanide concentration was accompanied by corresponding CCO inhibition and elevated MDA levels. Decrease in GSH levels was not followed by reciprocal change in GSSG levels. Diminution of SOD, GPx, GR and CA activity was congruent with elevated nitrite levels and upregulation of iNOS and UCP-2 expression, without any DNA damage. It was concluded that long-term cyanide exposure caused oxidative stress, accompanied by upregulation of iNOS. The upregulation of UCP-2 further sensitized the cells to cyanide and accentuated the oxidative stress, which was independent of DNA damage.

Aims: Protective efficacy of N-acetylcysteine (NAC) was assessed against sub-acute diisopropyl phosphorofluoridate (DFP) poisoning in mice. Main methods: Mice were allocated into nine groups of six each: vehicle control; DFP (0.125 LD50 approximate to 0.483 mg/ kg bwt, s.c.); DFP + Atropine (ATR, 10 mg/kg bwt, i.p., 0 min); DFP + Pralidoxime (2-PAM, 30 mg/kg bwt, i.m., 0 min); DFP + NAC (150 mg/kg bwt, i.p., - 60 min); DFP + ATR + NAC; DFP + 2-PAM + NAC; DFP + ATR + 2-PAM; and DFP + ATR + 2-PAM + NAC. Animals received various treatments for 21 d daily. Plasma butyrylcholinesterase (BChE) was measured after 7, 14 and 21 d of exposure. Brain acetylcholinesterase (AChE) and reduced glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), and superoxide dismutase (SOD) were measured (brain, liver and kidney) after 21 d of exposure. Histopathology, immunohistochemistry, and Western blot for inducible nitric oxide synthase (iNOS) and c-fos were also performed. Key findings: DFP significantly reduced BChE and AChE levels. Diminished GSH, CAT, SOD (brain and liver), GPx, GR, and elevated MDA (Brain) levels were also observed. DFP caused notable histopathology (brain, liver and kidney) and over expression of iNOS, and c-fos proteins (brain). NAC enhanced the protective efficacy of ATR and 2-PAM in most parameters, without any appreciable protection in iNOS and c-fos expression. Significance: NAC as an adjunct with ATR and 2-PAM, exhibited marked beneficial effects against sub-acute DFP poisoning, indicating its possible implications in the management of OP poisoning.

Cyanogens are widely used in industries and their toxicity is mainly due to cyanogenesis. The antidotes for cyanide are usually instituted for the management of cyanogen poisoning. The present study reports the protective efficacy of 14 carbonyl compounds and their metabolites, and nutrients (1.0 g/kg; oral; +5 min) against acute oral toxicity of acetonitrile (ATCN), acrylonitrile (ACN), malononitrile (MCN), propionitrile (PCN), sodium nitroprusside (SNP), succinonitrile (SCN), and potassium ferricyanide (PFCN) in rats. Maximum protection index was observed for alpha-ketoglutarate (A-KG) against MCN and PCN (5.60), followed by dihydroxyacetone (DHA) against MCN (2.79). Further, MCN (0.75 LD50) caused significant increase in cyanide concentration in brain, liver and kidney and inhibition of cytochrome c oxidase activity in brain and liver, which favorably responded to A-KG and DHA treatment. Up-regulation of inducible nitric oxide synthase by MCN, PCN and SNP, and uncoupling protein by PCN and SNP observed in the brain was abolished by A-KG administration. However, no DNA damage was detected in the brain. MCN and SNP significantly decreased the mean arterial pressure, heart rate, respiratory rate and neuromuscular transmission, which were resolved by A-KG. The study suggests a beneficial effect of A-KG in the treatment of acute cyanogen poisoning.

Objective: The aim of the study was to investigate the effect of an antioxidant, viz., N -acetylcysteine (NAC) against various biochemical and oxidative changes caused by acute diisopropyl phosphorofluoridate (DFP) poisoning in mice. Materials and Methods: Effect of NAC (150 mg/kg) alone or in conjunction with atropine (10 mg/kg; 0 min), and/or 2-PAM (30 mg/kg; 0 min) on (i) LD 50 of DFP, (ii) time for onset of signs and symptoms, and death after lethal doses of DFP, and (iii) time- dependent biochemical and oxidative damage after 0.50 LD 50 DFP was investigated in Swiss albino mice. Results: NAC (-60 min) did not confer any additional protection against DFP when measured by protection index (ratio of LD 50 of DFP in protected and unprotected animals). However, NAC (-60 min, 0 min or +5 min) with atropine/ and or 2-PAM significantly delayed the onset of signs and symptoms, and time of death after 2.0 LD 50 DFP. Further, NAC (-60 min) augmented the efficacy of atropine and 2-PAM in normalizing the butyrylcholinesterase and reduced glutathione levels in plasma, and acetylcholinesterase, malondialdehyde, glutathione peroxidase, catalase, and superoxide dismutase levels in brain. Conclusion: The study indicates beneficial role of NAC in mitigating the toxicity of OP.

Toxicity of organophosphates (OP) is mainly ascribed to inhibition of acetylcholinesterase (AChE) enzyme at the cholinergic synapses. This results in cholinergic crisis leading to various muscarinic, nicotinic and central effects. Additionally, there are several non-cholinergic effects of OP which are likely to exacerbate the toxicity and complicate diagnosis. The present study reports the dose (0.125 - 4.0 LD50) and time (1 h - 14 d)- dependent acute effect of diisopropyl phosphorofluoridate (DFP) on mice body weight, organ-body weight index (brain), butyrylcholinesterase (BChE) and β-glucoronidase (BG) activity in plasma, AChE activity, reduced glutathione (GSH) and malondialdehyde (MDA) levels in brain, and DNA damage in brain (agarose gel electrophoresis) and blood (comet assay). The study reveals a dose and time- dependent BChE inhibition up to 24 h and AChE inhibition up to 7 d. However, elevated BG levels were observed up to 1 h only after 1.0, 2.0, and 4.0 LD50 DFP. Diminished GSH levels up to 24 h and increased MDA levels at 4 h indicated oxidative stress. None of the treatments produced any DNA damage in soft tissues. In addition to cholinesterase, the study suggests possible relevance of measuring BG levels (non-cholinergic marker) in the diagnosis of OP poisoning.