Early glutathione intervention educed positive correlation between VGLUT1 expression and spatial memory in the Nω-nitro-L-arginine methyl rat model of IUGR.

INTRODUCTION: One of the most compelling causes of perinatal mortality and morbidity is intrauterine growth restriction (IUGR). IUGR is linked with numerous health challenges that last lifelong, including neurodevelopmental impairment and a high incidence of brain dysfunction. There is mounting evidence that places the glutamatergic system at the center of the neurobiology and treatment of neurological diseases. Therefore, this study investigated the effects of postnatal glutathione intervention on the spatial memory and the expressions of vesicular glutamate transporter 1 (VGLUT1) in the hippocampus and the cerebellar cortex of Nω-nitro-L-arginine methyl (L-NAME)-induced rat model of IUGR. MATERIALS AND METHOD: Twelve adult female rats were divided into Control and L-NAME groups; each containing 6 female rats. The control group received a single daily dose of normal saline while the L-NAME group was administered 50 mg/kg L-NAME daily from gestational day 9 until parturition. Offspring of the control rats were given free access to feeds while offspring from the L-NAME group were assigned into 3 groups: G1: given free access to feeds; G2 and G3 were administered 1.5 mg/kg body weight of glutathione from postnatal day (PND) 4-9 and PND 25-31 respectively. At the end of the intervention, Y-maze was conducted, and the rats euthanized on PND 35. The brain sections were processed, and immunofluorescence staining was performed using the Vectafluor Excel R.T.U Antibody kit. RESULTS: IUGR caused a significant 31.1% decrease in spontaneous alternation percentage (SAP), while early treatment with glutathione at PND 4-9 significantly (p < 0.01) increased SAP, while late treatment at PND 25-9 significantly decreased SAP compared to IUGR group. Furthermore, IUGR caused significant (p < 0.001) downregulation in corrected total cell fluorescence (CTCF) of VGLUT1 in both the hippocampus and cerebellar cortex. While treatment with glutathione caused upregulation in CTCF of VGLUT1 in the hippocampus and the cerebellar cortex. CONCLUSION: Our results showed that early intervention with glutathione has significant therapeutic potential via upregulation of VGLUT1 expression in both hippocampus and cerebellar cortex, which positively correlated with enhanced spatial memory in IUGR rat model.

Amyloid-beta (1-42) lesion of CA1 rat dorsal hippocampus reduces contextual fear memory and increases expression of microglial genes regulating neuroinflammation.

Emerging evidence indicates that the pathogenesis of Alzheimer's disease (AD) is not confined to neuronal disruptions but robustly communicates with the brain's immune system. Genome-wide analysis suggests that several genes, which increase the risk for AD, encode for factors that regulate the glial clearance of misfolded proteins and the inflammatory reaction. This study reappraises the amyloid hypothesis by focusing on the impact of neuroinflammation in a beta-amyloid model of AD, how this possibly exacerbates the disease's progression, and the correlation between genes regulating neuroinflammation (CD33 and TREM2) with post-training recall. Male Sprague-Dawley rats were used for this study, randomly divided into a vehicle group of rats (n = 40) that were infused with phosphate-buffered saline (PBS) and an Aß(1-42) group (n = 40) that were infused with the neurotoxin Aß(1-42) peptide. Fear conditioning test (FCT) to assess fear memory was conducted pre and post-lesion. The polymerase chain reaction was performed to determine the expression levels of CD33 and TREM2 genes. Our results show that Aß(1-42) lesion of the rat CA1 hippocampal subregion significantly reduces contextual fear memory, and this reduction was exacerbated as the post-lesion days increased. We also observed an increase in the expression levels of CD33 and TREM2 genes in the Aß(1-42) lesioned groups compared to their corresponding vehicle groups. Taken together, the behavioral and gene expression data provide inferential evidence that Aß(1-42) infusion impairs contextual memory by disrupting cellular pattern separation processes in the hippocampus, thus linking neuroinflammation to specific neural circuit disruption and cognitive deficit.

Memory decline correlates with increased plasma cytokines in amyloid-beta (1-42) rat model of Alzheimer's disease.

Dysregulation of inflammatory markers like cytokines is implicated in the pathophysiology of Alzheimer's disease (AD). Altered level of these cytokines show that pathogenesis of AD is beyond dysfunction of neurons resulting from amyloid beta accumulation but involves neuroinflammatory mechanisms elicited by the neuroimmune cell. In this study, we investigated the effect of amyloid-beta (1-42) (Aß(1-42)) on memory and how inflammatory markers respond to this model of AD. Male Sprague-Dawley rats were used for this study. The animals were randomly divided into four groups euthanized on day 3, 7, 10 and 14 post-lesion with amyloid-beta (5 µg/5 µl) while corresponding control groups were stereotaxically injected with a vehicle (5 µl of 0.01 M phosphate- buffered saline). The Morris water maze (MWM) test to access learning and memory was conducted pre and post-lesion and blood was collected through cardiac puncture on day 3, 7, 10 and 14 post lesion. Multiplex immunoassay was performed to determine the plasma levels of IL-1ß, IL-6, IL-10 and TNF-α. Our results showed impaired spatial memory and elevated plasma levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) with a concomitantly lowered level of the anti-inflammatory cytokine (IL-10) in the Aß(1-42) lesioned rats when compared to the vehicle groups. This study showed a negative correlation between the decline in performance of the spatial memory task and plasma levels of the pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α and positive correlation with the anti-inflammatory cytokine IL-10. In conclusion, this study most importantly demonstrated an association between progressive decline in spatial memory and increased plasma cytokine level induced by the infusion of Aß(1-42).