Ambiguous Contribution of Glucocorticosteroids to Acute Neuroinflammation in the Hippocampus of Rat.

Effects of modulation of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) on acute neuroinflammatory response were studied in the dorsal (DH) and ventral (VH) parts of the hippocampus of male Wistar rats. Local neuroinflammatory response was induced by administration of bacterial lipopolysaccharide (LPS) to the DH. The modulation of GR and MR was performed by dexamethasone (GR activation), mifepristone, and spironolactone (GR and MR inhibition, respectively). Experimental drugs were delivered to the dentate gyrus of the DH bilaterally by stereotaxic injections. Dexamethasone, mifepristone, and spironolactone were administered either alone (basal conditions) or in combination with LPS (neuroinflammatory conditions). Changes in expression levels of neuroinflammation-related genes and morphology of microglia 3 days after intrahippocampal administration of above substances were assessed. Dexamethasone alone induced a weak proinflammatory response in the hippocampal tissue, while neither mifepristone nor spironolactone showed significant effects. During LPS-induced neuroinflammation, GR activation suppressed expression of selected inflammatory genes, though it did not prevent appearance of activated forms of microglia. In contrast to GR activation, GR or MR inhibition had virtually no influence on LPS-induced inflammatory response. The results suggest glucocorticosteroids ambiguously modulate specific aspects of neuroinflammatory response in the hippocampus of rats at molecular and cellular levels.

Neuroinflammatory Cytokine Response, Neuronal Death, and Microglial Proliferation in the Hippocampus of Rats During the Early Period After Lateral Fluid Percussion-Induced Traumatic Injury of the Neocortex.

Time course of changes in neuroinflammatory processes in the dorsal and ventral hippocampus was studied during the early period after lateral fluid percussion-induced neocortical traumatic brain injury (TBI) in the ipsilateral and contralateral hemispheres. In the ipsilateral hippocampus, neuroinflammation (increase in expression of pro-inflammatory cytokines) was evident from day 1 after TBI and ceased by day 14, while in the contralateral hippocampus, it was mainly limited to the dorsal part on day 1. TBI induced an increase in hippocampal corticosterone level on day 3 bilaterally and an accumulation of Il1b on day 1 in the ipsilateral hippocampus. Activation of microglia was observed from day 7 in different hippocampal areas of both hemispheres. Neuronal cell loss was detected in the ipsilateral dentate gyrus on day 3 and extended to the contralateral hippocampus by day 7 after TBI. The data suggest that TBI results in distant hippocampal damage (delayed neurodegeneration in the dentate gyrus and microglia proliferation in both the ipsilateral and contralateral hippocampus), the time course of this damage being different from that of the neuroinflammatory response.

Neonatal Proinflammatory Stress and Expression of Neuroinflammation-Associated Genes in the Rat Hippocampus.

Differential effect of the neonatal proinflammatory stress (NPS) on the development of neuroinflammation in the hippocampus and induction of the depressive-like behavior in juvenile and adult male and female rats was studied. NPS induction by bacterial lipopolysaccharide in the neonatal period upregulated expression of the Il6 and Tnf mRNAs accompanied by the development of depressive-like behavior in the adult male rats. NPS increased expression of the mRNAs for fractalkine and its receptor in the ventral hippocampus of the juvenile male rats, but did not affect expression of mRNAs for the proinflammatory cytokines and soluble form of fractalkine. NPS downregulated expression of fractalkine mRNA in the dorsal hippocampus of juvenile males. No significant effects of NPS were found in the female rats. Therefore, the NPS induces long-term changes in the expression of neuroinflammation-associated genes in different regions of the hippocampus, which ultimately leads to the induction of neuroinflammation and development of depressive-like behavior in male rats.

CB2 receptors modulate seizure-induced expression of pro-inflammatory cytokines in the hippocampus but not neocortex.

We compared neuroinflammatory responses induced by nonconvulsive and convulsive seizures and analyzed the role that may be played by cannabinoid CB2 receptors in the neuroinflammatory response induced by generalized tonic-clonic seizures (GTCS). Using quantitative PCR, we analyzed expression of interleukin-1b, CCL2, interleukin-6, tumor necrosis factor (TNF), transforming growth factor beta 1 (TGFb1), fractalkine, and cannabinoid receptor type 2 in the neocortex, dorsal and ventral hippocampus, cortical leptomeninges, dura mater, and spleen in 3 and 6 h after induction of GTCS by a high dose of pentylenetetrazole (PTZ, 70 mg/kg) and absence-like activity by a low dose of PTZ (30 mg/kg). The low dose of PTZ had no effect on the gene expression 3 and 6 h after PTZ injection. In 3 and 6 h after high PTZ dose, the expression of CCL2 and TNF increased in the neocortex. Both ventral and dorsal parts of the hippocampus responded to seizures by elevation of CCL2 expression 3 h after PTZ. Cortical leptomeninges but not dura mater also had elevated CCL2 level and decreased TGFb1 expression 3 h after GTCS. Activation of CB2 receptors by HU308 suppressed an inflammatory response only in the dorsal hippocampus but not neocortex. Suppression of CB2 receptors by AM630 potentiated expression of inflammatory cytokines also in the hippocampus but not in the neocortex. Thus, we showed that GTCS, but not the absence-like activity, provoke inflammatory response in the neocortex, dorsal and ventral hippocampus, and cortical leptomeninges. Modulation of CB2 receptors changes seizure-induced neuroinflammation only in the hippocampus but not neocortex.

Glucocorticoids: Dr. Jekyll and Mr. Hyde of Hippocampal Neuroinflammation.

Glucocorticoids (GCs) are an important component of adaptive response of an organism to stressogenic stimuli, a typical stress response being accompanied by elevation of GC levels in blood. Anti-inflammatory effects of GCs are widely used in clinical practice, while pro-inflammatory effects of GCs are believed to underlie neurodegeneration. This is particularly critical for the hippocampus, brain region controlling both cognitive function and emotions/affective behavior, and selectively vulnerable to neuroinflammation and neurodegeneration. The hippocampus is believed to be the main target of GCs since it has the highest density of GC receptors potentially underlying high sensitivity of hippocampal cells to severe stress. In this review, we analyzed the results of studies on pro- and anti-inflammatory effects of GCs in the hippocampus in different models of stress and stress-related pathologies. The available data form a sophisticated, though often quite phenomenological, picture of a modulatory role of GCs in hippocampal neuroinflammation. Understanding the dual nature of GC-mediated effects as well as causes and mechanisms of switching can provide us with effective approaches and tools to avert hippocampal neuroinflammatory events and as a result to prevent and treat brain diseases, both neurological and psychiatric. In the framework of a mechanistic view, we propose a new hypothesis describing how the anti-inflammatory effects of GCs may transform into the pro-inflammatory ones. According to it, long-term elevation of GC level or preliminary treatment with GC triggers accumulation of FKBP51 protein that suppresses activity of GC receptors and activates pro-inflammatory cascades, which, finally, leads to enhanced neuroinflammation.

Cholinergic Deficit Induced by Central Administration of 192IgG-Saporin Is Associated With Activation of Microglia and Cell Loss in the Dorsal Hippocampus of Rats.

Alzheimer's disease (AD) is associated with degeneration of cholinergic neurons in the basal forebrain. Administration of the immunotoxin 192IgG-saporin to rats, an animal model of AD, leads to degeneration of cholinergic neurons in the medial septal area. In the present study, cholinergic cell death was induced by intracerebroventricular administration of 192IgG-saporin. One and a half months after injection, we studied the histopathology of the hippocampus and the responses of microglia and astrocytes using immunohistochemistry and neuroglial gene expression. We found that treatment with 192IgG-saporin resulted in neuronal loss in the CA3 field of the hippocampus. Microglial proliferation was observed in the dentate gyrus of the dorsal hippocampus and white matter. Massive proliferation and activation of microglia in the white matter was associated with strong activation of astrocytes. However, the expression of microglial marker genes significantly increased only in the dorsal hippocampus, not the ventral hippocampus. These effects were not related to non-specific action of 192IgG-saporin because of the absence of the Nerve growth factor receptor in the hippocampus. Additionally, 192IgG-saporin treatment also induced a decrease in the expression of genes that are associated with transport functions of brain vascular cells (Slc22a8, Ptprb, Sdpr), again in the dorsal hippocampus but not in the ventral hippocampus. Taken together, our data suggest that cholinergic degeneration in the medial septal area induced by intracerebroventricular administration of 192IgG-saporin results in an increase in the number of microglial cells and neuron degeneration in the dorsal hippocampus.