Decreased levels of nuclear glucocorticoid receptor protein in the hippocampus of aged Long-Evans rats with cognitive impairment.

Previous studies using animal models of cognitive aging showed that hypothalamic-pituitary-adrenal (HPA) responses to stress are impaired and glucocorticoid receptor (GR) mRNA is decreased in cognitively impaired aged rats, compared with those in young rats and cognitively unimpaired aged rats. Increased HPA activity is associated with the loss of hippocampal corticosteroid receptors. In the current investigation, GR expressions in the hippocampus were examined in young and aged male Long-Evans rats whose spatial memory was initially assessed on the Morris water maze task. We evaluated GR protein level in the hippocampus in young and aged rats characterized on the basis of the spatial task. In the hippocampus of aged rats with spatial memory impairments, GR protein level was decreased in the nucleus but not in the cytosol, and levels of glucocorticoid response elements binding activity was decreased. These results suggest that GR signaling is impaired in the hippocampus of rats with cognitive impairment. Impaired GR signaling may contribute to HPA axis dysfunction in aged rats and aged humans with cognitive impairment.

Decreased interactions in protein kinase A-glucocorticoid receptor signaling in the hippocampus after selective removal of the basal forebrain cholinergic input.

Removal of the cholinergic innervation to the hippocampus via selective immunolesions of septohippocampal cholinergic neurons induces dysfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis and decreases glucocorticoid receptor (GR) mRNA. This study examined whether removal of the cholinergic innervation decreased GR protein levels and induced changes in the interaction between GR and the cytoplasmic catalytic subunit of protein kinase A (PKAc) in the hippocampus. In lesioned animals, GR protein levels were markedly decreased in the nucleus, but not in the cytosol of hippocampal neurons, whereas mineralocorticoid receptor (MR) levels remained unchanged in both the nucleus and cytosol. PKAc levels did not differ between lesioned and control groups, but PKAc activity was reduced in lesion tissue compared with the controls. The interaction between GR and PKAc was also decreased in the hippocampus without cholinergic input. These results indicate that degeneration of septohippocampal cholinergic neurons leads to reduced PKAc activity in the hippocampus which, in turn, alters GR signaling. The altered GR signaling induced by the degeneration of basal forebrain cholinergic neurons may contribute to dysfunction of the HPA axis in aged animals and patients with Alzheimer's disease (AD) and lead to neuropsychiatric symptoms that occur throughout the course of AD.

Effects of Scutellaria baicalensis on chronic cerebral hypoperfusion-induced memory impairments and chronic lipopolysaccharide infusion-induced memory impairments.

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of the roots of Scutellaria baicalensis Georgi (Labiatae) have been widely used to relieve fever related to bacterial infection and inflammatory diseases in traditional Korean medicine and have been reported to be effective in brain diseases. These experiments were conducted to examine the effects of oral administration of Scutellaria baicalensis extracts on the rescue of memory impairments induced by chronic cerebral hypoperfusion or chronic lipopolysaccharide (LPS) infusion. In addition, the underlying mechanisms of these effects were investigated. MATERIALS AND METHODS: In the first experiment, chronic cerebral hypoperfusion was induced in male Wister rats by bilateral common carotid artery occlusion (BCCAo). Daily administration of Scutellaria baicalensis extracts was started on 20 day after BCCAo and given for 40 days. A Morris water maze was then used to evaluate the status of the hippocampal-dependent spatial learning and hippocampal mitogen-activated protein kinase (MAPK) signaling was examined in control rats, rats with chronic cerebral hypoperfusion, and rats with chronic cerebral hypoperfusion that was administered Scutellaria baicalensis. In the second experiment, hippocampal microglial activation was induced by chronic infusions of LPS into the fourth ventricle of Fisher-344 rat brains. Daily administration of Scutellaria baicalensis extracts was started on 7 day after the surgery of LPS infusion and given for 32 days. Spatial memory and hippocampal microglial activation was then examined in control rats with an artificial cerebrospinal fluid infusion, rats with chronic LPS infusion, and rats with chronic LPS infusion that were administered Scutellaria baicalensis. RESULTS: Rats that received chronic cerebral hypoperfusion or chronic LPS infusion showed spatial memory impairments relative to their control rats; however, these symptoms were reduced by daily administration of Scutellaria baicalensis. Administration of Scutellaria baicalensis mitigated alterations of hippocampal MAPK signaling by chronic cerebral infusion and microglial activation by chronic LPS infusion. CONCLUSIONS: These results indicate that Scutellaria baicalensis may possess therapeutic potential for the prevention of Alzheimer's disease and vascular dementia.

Differences in hippocampal CREB phosphorylation in trace fear conditioning of two inbred mouse strains.

The effects of genetic background on fear trace conditioning were evaluated in relation to phosphorylated levels of cAMP response element-binding protein (CREB) in the hippocampus using two different inbred strains of mice, C57BL/6 and DBA/2. The male mice received a trace fear conditioning protocol and unpaired control groups were included to assess nonassociative effects on test performance. Both C57BL/6 and DBA/2 mice with paired training displayed higher freezing responses during testing than those with unpaired training, respectively. The C57BL/6 mice with paired training also displayed higher freezing responses to the tone-CS during testing than the DBA/2 mice with paired training. Because much evidence implicates the hippocampus as an important neural substrate for trace fear conditioning, the engagement of the hippocampus was examined after testing by measuring levels of CREB and phosphorylated CREB (pCREB). The results revealed that hippocampal CREB levels in both strains of mice were not significantly altered according to the type of training (unpaired vs. paired). However, the hippocampal pCREB levels were significantly higher in the paired training group than the unpaired control group in C57BL/6 mice, but not in DBA/2 mice. These findings indicate that hippocampal pCREB is closely tied to this form of associative conditioning only in C57BL/6 mice and that different neural substrates may support trace conditioning in C57BL/6 and DBA/2 strains.

Macelignan attenuates activations of mitogen-activated protein kinases and nuclear factor kappa B induced by lipopolysaccharide in microglial cells.

A previous study showed that macelignan extracted from Myristica fragrans has anti-inflammatory properties using hippocampal neuronal and primary microglial cells. Subsequently, a study using animals with chronic lipopolysaccharide (LPS) infusion into the brain showed that oral treatments of macelignan reduced the hippocampal microglial activation and hippocampal-dependent spatial memory impairments induced by LPS. However, the molecular mechanisms responsible for the anti-inflammatory activity of macelignan have not been elucidated in the microglia. Therefore, the present study was conducted to determine if mitogen-activated protein kinase (MAPK) signaling and nuclear factor-kappa B (NF-kappaB) activities are related to the anti-inflammatory effects of macelignan on LPS-stimulated BV-2 microglial cells. The results show that macelignan suppresses both the phosphorylations of MAPKs and the degradation of inhibitory-kappa B (IkappaBalpha) and increases of nuclear NF-kappaB in LPS-stimulated BV-2 microglial cells. These results suggest that macelignan has an anti-inflammatory effect on the affected brain through regulation of the inflammation through the MAPK signal pathway.

Macelignan attenuates LPS-induced inflammation and reduces LPS-induced spatial learning impairments in rats.

Previous studies have shown that macelignan has anti-inflammatory and neuroprotective effects. Subsequently, in the current study, we demonstrate that oral administrations of macelignan reduce the hippocampal microglial activation induced by chronic infusions of lipopolysaccharide (LPS) into the fourth ventricle of Fisher-344 rat brains. A Morris water maze was used to evaluate the status of the hippocampal-dependent spatial learning in control rats with an artificial cerebrospinal fluid infusion, rats with chronic LPS infusions, and rats with chronic LPS infusions and oral administrations of macelignan. The rats with chronic LPS infusions showed spatial memory impairments relative to the control rats in the performance of the memory task. Daily administration of macelignan reduced the spatial memory impairments induced by the chronic LPS infusions. The results indicate that macelignan may possess therapeutic potential for the prevention of Alzheimer's disease.

Dexibuprofen (S(+)-isomer ibuprofen) reduces microglial activation and impairments of spatial working memory induced by chronic lipopolysaccharide infusion.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been proposed as a therapeutics to reduce the risk of Alzheimer's disease (AD). The present study shows that the peripheral administration of dexibuprofen (S(+)-isomer ibuprofen), which causes less gastric damage and has better anti-inflammatory effects than ibuprofen, reduces the microglial activation in the cortex and hippocampus, and reduces the phosphorylation of extracellular signal-regulated kinases in the hippocampus, which has been induced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle of Wistar rats. The effects of dexibuprofen on impairments of spatial working memory induced by LPS infusions were measured with a trial-unique matching-to-place task in a water maze which assessed memory for place information over varying delays. When performing the water maze task, the rats with the LPS infusions showed spatial working memory impairments relative to the rats with the artificial cerebrospinal fluid. Daily administrations of dexibuprofen reduced the spatial working memory impairment induced by the chronic LPS infusion. The results indicate that NSAID treatments using dexibuprofen significantly attenuate the processes that drive the pathology associated with AD and that this process may involve the suppression of microglial activation.

SK-PC-B70M from Pulsatilla koreana improves scopolamine-induced impairments of memory consolidation and spatial working memory.

Previous studies have shown that hederacolchiside-E from Pulsatilla koreana has neuroprotective effects and cognition-enhancing effects. Subsequently, in the current study, we demonstrate that oral administrations of oleanolic-glycoside saponins enriched fraction from P. koreana, designated as SK-PC-B70M, improve impairments in memory consolidation and spatial working memory by systemic injection of scopolamine, a muscarinic cholinergic receptor antagonist. In a step-through avoidance task, when the rats stepped through a dark chamber in a shuttle box, an electric shock was given and then SK-PC-B70M was administered 30 min later. Twenty-four hours later, the rats were placed in an illuminated chamber. The rats with SK-PC-B70M treatments showed longer response latencies than rats with only scopolamine. Spatial working memory was measured with a trial-unique matching-to-place task in a water maze which assessed memory for place information over varying lengths of delays. Three delay lengths were used: 1 min, 5 min, and 3 h. In comparison with the control rats, the rats with scopolamine treatments took significantly longer to find the platform in the second trial with 1- and 5-min delays. The rats with both scopolamine and SK-PC-B70M had significantly less search error compared with the rats with scopolamine only. These findings indicate that SK-PC-B70M has effects on reversing impairments of memory consolidation and working memory impairments induced by scopolamine.