The effects of repetitive stress on tat protein-induced pro-inflammatory cytokine release and steroid receptor expression in the hippocampus of rats

Abstract

Human immunodeficiency virus type 1 (HIV-1) affects the central nervous system (CNS) that may lead to the development of HIV-associated neuropathologies. Tat protein is one of the viral proteins that have been linked to the neurotoxic effects of HIV. Since many individuals living with HIV often experience significant adverse circumstances, the present study investigated whether exposure to stressful conditions would exacerbate harmful effects of tat protein on brain function. Tat protein (10 μg/10 μl) was injected bilaterally into the dorsal hippocampus of the animal using stereotaxic techniques. The control group received an injection of saline (10 μl). Some control and tat protein-treated animals were subjected to restrain stress for 6 h per day for 28 days and compared to a non-stress group. All animals underwent two behavioural tests, the open field test (OFT) and the novel object recognition test (NORT) to assess their mood state and cognitive function respectively. The release of pro-inflammatory cytokines (TNF-α and IL-1β) and the expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors were also measured to see whether the impact of the repetitive stress on Tat protein-induced behavioural effects was mediated by elements of the immune system and the HPA axis. Rats treated with tat protein showed the following behavioural changes when compared to control animals: there was a significant decrease in time spent in the center of the open field during the OFT, a significant reduction in time spent with the novel object during the NORT, but no change in locomotor activity. Real-time PCR data showed that the expression levels of GR and MR mRNA were significantly reduced, while Western blot analysis showed that the protein expression levels of TNF-α and IL-1β were significantly increased. The present findings indicated that injection of tat protein into the hippocampus of rats not subjected to stress may lead to anxiety-like behaviour and deficits in learning and memory. Tat-treated animals subjected to stress evoked only a modest effect on their behaviour and neurochemistry, while stress alone led to behavioural and neurochemical changes similar to tat protein.

Tight junction proteins in the small intestine and prefrontal cortex of female rats exposed to stress of chronic isolation starting early in life

“…The decreased gene expression of MR in the prefrontal cortex observed in placebo-treated rats exposed to chronic stress of post-weaning social isolation has not been described yet but the finding is consistent with downregulation of brain MR described in several other chronic stress models mainly in the hippocampus. [30][31][32] As MR expression has direct protective effects at a neuronal level, 33 The results of behavioral measurements in the present study are fully in agreement with the well-known anxiogenic effects of chronic social isolation starting early in life, which were mainly described in male rodents. As this study was performed in female rats, the results add further support to increased anxiety-like behavior, reflected by both traditional spatiotemporal and ethological indices of anxiety induced by social isolation in females.…”

“…The decreased gene expression of MR in the prefrontal cortex observed in placebo‐treated rats exposed to chronic stress of post‐weaning social isolation has not been described yet but the finding is consistent with downregulation of brain MR described in several other chronic stress models mainly in the hippocampus 30–32 . As MR expression has direct protective effects at a neuronal level, 33 the chronic stress‐induced downregulation of the MR in the brain could affect neuronal integrity.…”

High dose of dexamethasone protects against EAE-induced motor deficits but impairs learning/memory in C57BL/6 mice

“…Also, overexpression of the dominant negative form of GR in the hippocampus reversed the learning and memory deficits in DEX-treated EAE animals at the asymptomatic phase, confirming that GR transcriptional activity in an inflammatory environment is essential for the cognitive impairment in EAE. It is, therefore, imperative to know whether this modulation depends on the other areas of the limbic system and glial cells, which have a crucial role in neuroinflammation and synaptic plasticity 52,53 .…”

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

“…HIV-1 Tat also contains a cysteine-rich domain containing highly conserved cysteine residues that are critical for disulfide-bond formation (amino acids [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. We also observed a loss of suppression of β-catenin activity by a C31R Tat mutant in the presence or absence of morphine (Fig 4B and 4C).…”

“…In addition to cytotoxic effects due to direct infection with HIV-1, the CNS represents an environment where secreted viral proteins, cytokines, chemokines, and small molecules can all contribute to neurotoxicity [4,[27][28][29][30][31]. Therefore, proximity to HIV-1 infected cells can result in cell and tissue damage.…”