Protective effects of docosahexaenoic acid supplementation on cognitive dysfunction and hippocampal synaptic plasticity impairment induced by early postnatal PM2.5 exposure in young rats.

PM2.5 exposure is a challenging environmental issue that is closely related to cognitive development impairment; however, currently, relevant means for prevention and treatment remain lacking. Herein, we determined the preventive effect of docosahexaenoic acid (DHA) supplementation on the neurodevelopmental toxicity induced by PM2.5 exposure. Neonatal rats were divided randomly into three groups: control, PM2.5, and DHA + PM2.5 groups. DHA could ameliorate PM2.5-induced learning and memory dysfunction, as well as reverse the impairment of hippocampal synaptic plasticity, evidenced by enhanced long-term potentiation, recovered synaptic ultrastructure, and increased expression of synaptic proteins. Moreover, DHA increased CREB phosphorylation and BDNF levels and attenuated neuroinflammation and oxidative stress, reflected by lower levels of IBA-1, IL-1ß, and IL-6 and increased levels of SOD1 and Nrf2. In summary, our findings demonstrated that supplementation of DHA effectively mitigated the cognitive dysfunction and synaptic plasticity impairment induced by early postnatal exposure to PM2.5. These beneficial effects may be attributed to the upregulation of the CREB/BDNF signaling pathway, as well as the reduction of neuroinflammation and oxidative stress.

Autoimmune encephalitis after Japanese encephalitis in children: A prospective study.

OBJECTIVE: To explore anti-neuronal surface antibodies and identify associated serum predictors of autoimmune encephalitis after Japanese encephalitis (JE). METHODS: This prospective study first detected anti-neuronal surface antibodies and cytokines in the serum and cerebrospinal fluid (CSF) of JE patients within one week of symptom onset. Anti-neuronal surface antibodies and cytokines in the serum were detected on day 21 post-JE. If the patients relapsed during the convalescent phase, we simultaneously detected JE virus RNA and cytokines in the CSF, as well as anti-neuronal surface antibodies in the serum and CSF. RESULTS: All 31 patients were negative for anti-neuronal surface antibodies at the onset of JE in the serum and CSF. During the convalescent phase, five patients developed autoimmune encephalitis (two had anti-N-methyl-d-aspartate receptor [NMDAR] antibodies, one had γ-aminobutyric acid-B receptor [GABABR] antibodies, and two had other antibodies against unknown neuronal surface antigens). Patients who developed autoimmune encephalitis experienced more severe outcomes than those who did not at the one-year follow-up (p = 0.044). The levels of serum CXCL13 and IL-6, as well as CXCL13, BAFF, CXCL10, and MMP-9 in the CSF were increased in the convalescent phase compared to the acute phase in patients who developed autoimmune encephalitis (p < 0.05). CONCLUSION: In addition to anti-NMDAR antibodies, anti-GABABR antibodies and antibodies against unknown neuronal surface antigens can trigger autoimmune encephalitis following JE. Patients who developed autoimmune encephalitis had a poorer prognosis at the one-year follow-up. Serum CXCL13 may represent a predictor of autoimmune encephalitis after JE.

[Toxicity of dibutyl phthalate in primary cultured rat hippocampal neurons and the toxicological mechanism].

OBJECTIVE: To investigate the neurotoxicity and toxicological mechanism of dibutyl phthalate (DBP) in primary cultured rat hippocampal neurons. METHODS: Primary rat hippocampal neurons cultured for 4 days were exposed to 1 g/L DBP for 24, 48, or 96 h. Immunofluorescence assay and transmission electron microscopy (TEM) were used to observe the morphological changes of the axons and the ultrastructure of DBP-treated neurons. The action potential (AP) of the hippocampal neurons was measured with patch-clamp electrophysiology. CCK-8 assay was used to detect the viability of the hippocampal neurons, and Western blotting was performed to determine the mRNA and protein expressions of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY) and estrogen receptor ß (ERß). High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was employed to detect the release of the neurotransmitter GABA. RESULTS: After exposure to DBP for 96 h, the cellular network of the hippocampal neurons became sparse, and the neurons showed significantly decreased axonal length (P < 0.01) and presented with round cell nuclei, chromatin aggregation and cytoplasmic vacuolization. Patch-clamp electrophysiology revealed depolarization drift and increased frequency of discharge in the exposed neurons (P < 0.01). The neurons with DBP exposure for 24, 48 and 96 h all showed significantly decreased cell viability (P < 0.01). DBP exposure for 48 and 96 h significantly lowered the protein expressions of ERß, BDNF and NPY, and a 96-h exposure significantly reduced the release of the neurotransmitter GABA in the neurons (P < 0.05). CONCLUSIONS: DBP exposure causes morphological and functional damages of primary cultured rat hippocampal neurons. DBP-induced neurotoxicity is probably associated with GABA-mediated blockage of the ERß-BDNF-NPY signaling communication.

Effects of early postnatal exposure to fine particulate matter on emotional and cognitive development and structural synaptic plasticity in immature and mature rats.

INTRODUCTION: Fine particulate matter (PM2.5) is closely associated with many neurological disorders including neurodegenerative disease, stroke, and brain tumors. However, the toxic effects of PM2.5 on neurodevelopment remain unclear. In this study, we aimed to determine the neurotoxic effects of early postnatal exposure to PM2.5 in immature and mature rats. METHODS: We exposed neonatal rats to PM2.5 (2 or 10 mg/kg body weight) through intranasal instillation from postnatal day (PND) 3-15, once a day. Emotional and cognitive development were evaluated using the elevated plus maze, forced swimming, and Morris water maze tests. Hippocampal tissue was collected and subjected to transmission electron microscopy observation and western blot analysis. RESULTS: Rats had lower body weight after exposure to high dose of PM2.5. The behavioral test results indicated that high-dose PM2.5 exposure led to increased anxiety-like symptoms in immature and mature rats, apparent depressive-like behaviors in mature rats, and impaired spatial learning and memory abilities in immature rats, and low-dose PM2.5 exposure increased anxiety-like behaviors in immature rats. Further, high-dose PM2.5 exposure contributed to fewer synapses, thinner postsynaptic density, and shorter active zone in immature and mature rats, and also decreased expressions of synaptophysin (SYP), growth associated protein-43 (GAP43), and postsynaptic density-95 (PSD95) in immature rats, SYP and PSD95 in mature rats. Moreover, low-dose PM2.5 exposure diminished the expression of PSD95 in immature rats. In addition, high-dose PM2.5 exposure reduced brain-derived neurotrophic factor (BDNF) expression and cAMP response element binding protein (CREB) phosphorylation in both immature and mature rats, and low-dose PM2.5 exposure lessened BDNF expression and CREB phosphorylation in immature rats. CONCLUSIONS: Our findings indicate that PM2.5 impairs emotional and cognitive development by disrupting structural synaptic plasticity, possibly via the CREB/BDNF signaling pathway.

Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats.

Despite remarkable advances in epilepsy research, prevention and reversal of cognitive deficits following epilepsy remain a challenge. It was reported that the Rho kinase (ROCK) inhibitor fasudil hydrochloride (FH) could improve cognitive deficits in animal models of Alzheimer's disease (AD). Thus, the aim of the present study was to determine whether FH-mediated inhibition of the effects of ROCK signaling could improve cognitive deficits in male rats (postnatal 21-day old) following status epilepticus (SE) induced by lithium-pilocarpin, the therapeutic window of opportunity and to elucidate the underlying mechanisms. Western blotting analysis showed upregulation of phosphorylated RhoA (p-RhoA) expression, and indicated activation of Rho/ROCK signaling after SE. The Morris water maze (MWM) test was used to analyze learning-memory ability. HE staining, immunofluorescence staining with antineuronal nuclei (NeuN) and anti-neurofilament proteins 200 kD (NF200), transmission electron microscopy, and quantitative analysis of NeuN and synaptophysin by western blotting were performed to observe alterations in neurons, axons, and synapses in the hippocampi. Electroencephalogram (EEG) monitoring was used to record electrophysiological activities after SE. Our results indicated that treatment with FH at the first day following SE or 5 days later both could ameliorate cognitive dysfunction by reducing neuron, axon, and synapse damage, and mitigating EEG discharges, suggesting various roles for the Rho/ROCK signaling pathway in the pathological processes of brain damages following SE induced by lithium-pilocarpine. The Rho/ROCK signaling pathway is, therefore, a potential therapeutic target for the prevention or reversal of epilepsy induced brain damages.