Nanoparticles exacerbate methamphetamine neurotoxicity in hot and cold environment

Methamphetamine (METH) is increasingly being abused by people living in warm or cold environment resulting in abnormal behavioral or unsocial activities. In several areas where METH is consumed by people that are also exposed to wide variety of nanoparticles (NPs) from the environment or industrial sources making them more vulnerable to METH Induced adverse brain functions and behaviors. Thus, efforts are needed to find out possible therapeutic interventions to attenuate METH effects on brain and behavior in such individuals to contain their violent or unsocial activities. Previous experiments from our laboratory showed that engineered NPs from metals e.g., Ag or Cu enhanced METH neurotoxicity in rats given at 21°C. However, whether NPs intoxication at warm or cold environment could also exacerbate METH neurotoxicity or behavioral disturbances are not well known. Administration of METH (9 mg/kg, s,c,) in rats at high temperature (29° C) induces exacerbation of the blood-brain barrier (BBB), brain edema and cell injuries in rats as compared to METH given at 21°C. This suggests that heat stress induces greater neurotoxicity of METH. However effects of cold stress on METH neurotoxicity are still unclear. In present investigation, we examined METH (9 mg/kg, s.c.) in naïve rats either at 4°, 21° or 34° °C and induced BBB breakdown, brain edema and neuronal injuries after 3 h using standard protocol. In separate sets of animals (n=5) METH was given on the 8^th day in rats exposed to either SiO2, Cu or Ag NPs (50-60 nm, 50 mg/kg, i.p. for 7 days) at 4°, 21° or 34°C. The naïve animals exhibited marked BBB breakdown to Evans blue albumin (EBA) and radioiodine in several brain areas associated with brain edema formation and neuronal injuries after METH at 21°C. This was further enhanced by 120 to 180 % at 34°C but no brain pathology occurred at 4°C. However, NPs treated rats exhibited a 2- to 4-fold increase in brain pathologies after METH at 21°C, 4-to 6 fold increase at 34°C and 3- to 4-fold increase at 4°C. Interestingly, SiO2 exposure showed the most pronounced brain pathology by METH at all temperature ranges followed by Ag and Cu NPs. Pretreatment with a potent antioxidant compound H-290/51 (50 mg/kg, p.o. 30 min before METH, Astra Zeneca Mölndal, Sweden) significantly reduced brain pathology in naïve animals at 21°C and 34°C. However, in NPs treated group repeated exposure of H-290/51 (-30 min, 0 min and +30 min) was needed to attenuate METH induced brain pathology in all groups. These observations are the first to show that NPs aggravate METH induced brain pathology in cold or hot environments alike and timely intervention with antioxidant H-290/51 has neuroprotective effects.