The role of iNOS expression in cognitive impairment caused by lead exposure

Introduction The effect of lead on spatial memory has been widely confirmed. Inducible nitric oxide synthase (iNOS) is a key enzyme in inflammatory responses that is significantly upregulated upon microglia activation. However, prior to this study, there has been no direct evidence that iNOS mediates excitatory toxicity. Methods Sprague-Dawley rats (SD rats) were given ad libitum access to drinking water containing lead (Pb, 100 mg/L) from postnatal day (PND) 24 to 45, and each treatment group was paired with a supplement group that received either minocycline or S-methylisothiourea (SMT) via the corresponding administration route. Results The results showed a significant difference in spatial memory and induction of hippocampal long-term potentiation (LTP) in the Pb exposure group when compared with controls. Simultaneously, Pb exposure also caused hippocampal microglia activation, iNOS expression, and neuronal apoptosis. Furthermore, the expression levels of syntaphilin (SNPH) and synaptophysin (Syp) were significantly decreased after lead exposure, along with glutamate accumulation in the cerebrospinal fluid (CSF). Further studies revealed that minocycline administration significantly inhibited microglia activation and subsequent iNOS expression, which was accompanied by a decrease in neuronal apoptosis, reversal of the expression of SNPH and Syp, reduction in glutamate accumulation, and significant improvement in the induction of synaptic plasticity and learning and memory ability. Furthermore, after SMT specifically inhibited the expression of iNOS, the observed effects were significantly reversed. Discussion This study presents new evidence suggesting that the upregulated expression of microglial iNOS upon lead exposure may lead to lower expression levels of synaptic-associated proteins syntaphilin and synaptophysin. Subsequently, this may result in the accumulation of glutamate, neuronal damage, and synaptic plasticity impairment, ultimately leading to cognitive dysfunction.