Glutathione (GSH) is a key antioxidant that plays an important neuroprotective role in the brain. Decreased GSH levels are associated with neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Here we show that a diurnal fluctuation of GSH levels is correlated with neuroprotective activity against oxidative stress in dopaminergic cells. In addition, we found that the cysteine transporter excitatory amino acid carrier 1 (EAAC1), which is involved in neuronal GSH synthesis, is negatively regulated by the microRNA miR-96-5p, which exhibits a diurnal rhythm. Blocking miR-96-5p by intracerebroventricular administration of an inhibitor increased the level of EAAC1 as well as that of GSH and had a neuroprotective effect against oxidative stress in the mouse substantia nigra. Our results suggest that the diurnal rhythm of miR-96-5p may play a role in neuroprotection by regulating neuronal GSH levels via EAAC1.

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It has been shown that norepinephrine (NE) can mediate vasodilatation by stimulating the production of nitric oxide (NO) in brown adipose tissue (BAT), resulting in an increase in BAT blood flow. We speculated that constitutive NO synthase (NOS) is involved in this NO production. However, it is not known whether constitutive NOS is expressed in BAT. To answer this question, we assessed the expression of two types of constitutive NOS, endothelial (eNOS) and neuronal NOS (nNOS), in BAT of rats. eNOS was abundantly expressed in both BAT and isolated brown adipocytes, whereas nNOS was not. Cold exposure, which is known to stimulate NE release from sympathetic nerve terminals in BAT, led to a significant increase in eNOS mRNA in this tissue. In contrast, very low levels of inducible NOS (iNOS) mRNA were expressed, and cold stimulation failed to increase iNOS mRNA levels in BAT. These results suggest that eNOS is the primary isoform that is responsible for NO production in BAT and that its expression may be under sympathetic control.

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The physiological control of the expression of the genes for the alpha1-adrenoceptor subtypes was examined in rat brown adipose tissue by analysing Northern blots of poly(A)-enriched RNA with oligonucleotide probes. In control rats, alpha1B-receptor gene expression was much lower in brown adipose tissue than in liver, but the expression of both alpha1A and alpha1D was higher than in the heart, making brown adipose tissue one of the mammalian tissues with the highest expression of these subtypes. During acute exposure to cold, alpha1B-receptor gene expression was essentially unchanged, alpha1A-receptor gene expression was increased and alpha1D-receptor gene expression was transiently decreased. Noradrenaline injection could mimic these effects of acute cold exposure, indicating that the physiologically induced up- and down-regulations were due to the interaction of noradrenaline with cells within the tissue. In chronically cold-acclimated animals, alpha1B-receptor gene expression was decreased but that of the alpha1A-receptor gene remained at a level twice that of controls. alpha1D-Receptor gene expression was also somewhat decreased. It is suggested that the enhanced expression of the alpha1A-receptor gene explains the increased alpha1-receptor density in recruited brown adipose tissue reported previously. The intricate and differential regulation of alpha1-receptor gene expression and the markedly enhanced expression of the alpha1A-receptor may imply that alpha1-receptors are important for the recruitment process or for maintenance of the recruited state in this tissue.

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