Postnatal melatonin treatment protects against affective disorders induced by early-life immune stimulation by reducing the microglia cell activation and oxidative stress.

BACKGROUND: Systemic inflammation induced by neonatal infection may result as long-term hyper-activation of microglial cells followed by an overproduction of pro-inflammatory cytokines, such as tumor necrosis factor-alpha, nitric oxide and lipid peroxidation. Those inflammation mediators can trigger behavioral disruption and/or cognitive disorders. OBJECTIVE: The present work aims to evaluate the effect of melatonin (a cytokine release modulator and antioxidant agent) in the reduction of the prefrontal microglia activation and depressive-like behaviors induced by lipopolysaccharide (LPS) injection in adult rats. RESULTS: The effect of melatonin (5 mg/kg) was compared to minocycline (50 mg/kg), a well-known anti-inflammatory drug with potent inhibitory effect on microglial activation. Our results showed that LPS injection induced a significant increase in prefrontal cortex tumor necrosis factor-alpha and nitric oxide levels. Furthermore, lipid peroxidation and microglial activation were highly increased in the prefrontal cortex compared to control. The melatonin treatment induced a significant decrease on nitric oxide and lipid peroxidation levels in the prefrontal cortex and significant decrease on tumor necrosis factor-alpha and microglia activation. Melatonin can also induce a significant reduction in the anxiety and depression-like effect induced by PND9 LPS administration. CONCLUSION: Our results demonstrated that melatonin possesses potent protective effect against the depression and anxiety induced by LPS. The underlying effect of melatonin is probably due to the reduction of nitric oxide toxic effect and lipid peroxidation in addition to its anti-inflammatory effect.

Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE.

Magnetic resonance imaging (MRI) is of great utility in diagnosis and monitoring of multiple sclerosis (MS). Axonal loss is considered the main cause of accumulating irreversible disability. MRI using ultrasmall-super-paramagnetic-iron-oxide (USPIO) nanoparticles is a new technique to disclose in vivo central nervous system (CNS) inflammatory lesions infiltrated by macrophages in experimental autoimmune encephalomyelitis (EAE). Here, we raised the question of whether USPIO-enhanced MRI could serve as a tool to predict disease severity. We investigated, in a relapsing EAE model with various degrees of disease severity, the interindividual differences at the beginning of CNS inflammation as revealed in vivo by MRI with USPIO in correlation to the severity of both acute and chronic tissue damage including axonal loss. At the onset of the disease, observation of MRI alterations with USPIO allowed assignment of animals into USPIO+ and USPIO- groups. In 54.5% of diseased rats, MRI with USPIO+ at first attack revealed signal abnormalities mainly localized in the brainstem and cerebellum. Although animals did not present any clinically significant differences during the first attack, USPIO+ rats presented significantly more important tissue alterations at the first attack (onset and initiated recovery phase) and, at the second attack, more severe clinical disease with axonal loss compared to USPIO- rats. MRI lesion load and volume at the first attack correlate significantly with inflammation, macrophage recruitment, demyelination, acute axonal damage and, at the second attack, extent of axonal loss. This new MRI application of in vivo monitoring of macrophage infiltration provides a new platform to investigate the severity of inflammatory demyelinating CNS diseases.

In vivo damage of CNS myelin and axons induced by peroxynitrite.

In multiple sclerosis (MS) the mechanisms of injury caused by peroxynitrite remain uncertain. To study histological, ultra structural and molecular alterations caused by peroxynitrite in brain, the peroxynitrite donor 3-morpholinosydnonimine was injected in rat corpus callosum. Peroxynitrite induces strong primary axonal damage with characteristics of primary acute axonopathy, together with severe myelin alteration, myelin vacuolation and demyelination, and nitrotyrosine formation as confirmed by detection of nitrosated target proteins. Administration of the peroxynitrite scavenger uric acid inhibited these effects. In vivo, peroxynitrite leads to a disorganisation of myelin and to axonal damage presenting some similarities to the formation of MS lesions. Understanding the action of peroxynitrite in this process will open new therapeutic strategies by specific inhibition of peroxynitrite formation and action.