Amlodipine limits microglia activation and cognitive dysfunction in aged hypertensive mice.

BACKGROUND: SBP and blood pressure variability are independent risk factors for cerebral small vessel disease, a leading cause for stroke and dementia. Calcium-channel blockers are known to reduce blood pressure variability and may thus offer benefit against dementia. Beyond this effect, the impact of calcium-channel blockers on hypertension-induced neuroinflammation, and especially, microglial phenotype remains unknown. We aimed to study the ability of amlopidine to alleviate microglia inflammation, and slow down cognitive dysfunction in aged hypertensive mice. METHODS: Hypertensive BPH/2J and normotensive BPN/3J mice were studied until 12 months of age. Hypertensive mice were untreated or received amlodipine (10 mg/kg per day). Blood pressure parameters were measured by telemetry and tail cuff plethysmography. Mice underwent repeated series of cognitive tasks. Brain immunohistochemistry was performed to study blood-brain barrier dysfunction and microglial pro-inflammatory phenotype (CD68 + Iba1 + cells; morphological analysis). RESULTS: Amlodipine normalized SBP over the entire life span and decreased blood pressure variability. BPH/2J mice exhibited impaired short-term memory that was prevented by amlodipine at 12 months (discrimination index 0.41 ±â€Š0.25 in amlodipine-treated vs. 0.14 ±â€Š0.15 in untreated BPH/2J mice, P  = 0.02). Amlopidine treatment of BPH/2J did not prevent blood-brain barrier leakage, a measure of cerebral small vessel disease, but limited its size. Microglia's inflammatory phenotype in BPH/2J, characterized by an increased number of Iba1 + CD68 + cells, increased soma size and shortened processes, was partly reduced by amlodipine. CONCLUSION: Amlodipine attenuated the short-term memory impairment in aged hypertensive mice. Beyond its blood pressure lowering capacity, amlodipine may be cerebroprotective by modulating neuroinflammation.

Fetal asphyxia leads to a decrease in dorsal raphe serotonergic neurons.

The aim of the present study was to determine the effects of fetal asphyxia (FA) on anxiety and serotonergic neurons in young adult and middle-aged rats. FA was induced at embryonic day 17 by clamping the uterine circulation for 75 min. Anxiety-related behavior was tested in an open field, and design-based stereology was used for counting serotonergic (5-hydroxytryptamine/serotonin, 5-HT) neurons in the dorsal raphe nucleus (DRN). The open field revealed increased anxiety in the 19-month-old FA rats in comparison to control animals. No significant differences were found in DRN 5-HT neuron numbers at 6 months. At 19 months, however, FA significantly lowered the mean density and volume of 5-HT neurons in the DRN as compared to controls. Further, an age-related reduction was found in the total number, the mean density and the mean volume of 5-HT neurons within the FA group. In conclusion, FA is associated with increased anxiety and age-related changes in 5-HT immunohistochemistry within the DRN. These results support the notion that insults caused by asphyxiation during critical periods of brain development could create a predisposition to serotonergic abnormalities and anxiety deficits in adulthood.

Detection of amyloid beta aggregates in the brain of BALB/c mice after Chlamydia pneumoniae infection.

Neuroinflammation, initiated by cerebral infection, is increasingly postulated as an aetiological factor in neurodegenerative diseases such as Alzheimer's disease (AD). We investigated whether Chlamydia pneumoniae (Cpn) infection results in extracellular aggregation of amyloid beta (Abeta) in BALB/c mice. At 1 week post intranasal infection (p.i.), Cpn DNA was detected predominantly in the olfactory bulbs by PCR, whereas brains at 1 and 3 months p.i. were Cpn negative. At 1 and 3 months p.i., extracellular Abeta immunoreactivity was detected in the brain of Cpn-infected mice but also in the brain of mock-infected mice and mice that were neither Cpn infected nor mock infected. However, these extracellular Abeta aggregates showed morphological differences compared to extracellular Abeta aggregates detected in the brain of transgenic APP751(SL)/PS1(M146L) mice. These data do not unequivocally support the hypothesis that Cpn infection induces the formation of AD-like Abeta plaques in the brain of BALB/c mice, as suggested before. However, future studies are required to resolve these differences and to investigate whether Cpn is indeed an etiological factor in AD pathogenesis.

Cognition- and anxiety-related behavior, synaptophysin and MAP2 immunoreactivity in the adult rat treated with a single course of antenatal betamethasone.

We investigated the effects of a single course of antenatal betamethasone on cognition- and anxiety-related behavior and synaptophysin and microtubule-associated protein 2 (MAP2) immunoreactivity in the adult rat hippocampus. On d 20 of gestation, pregnant rats were injected with either 1) 170 microg/kg body weight of betamethasone ("clinically equivalent dose," equivalent to 12 mg twice, 24 h apart); 2) half this dose; or 3) vehicle. Cognition- and anxiety-related behavior of the offspring was analyzed at an age of 5 mo using the Morris water maze, object recognition task, and open field test. Subsequently, synaptophysin and MAP2 immunoreactivity were measured in the hippocampus. We report no detrimental effects of antenatal betamethasone on cognition- and anxiety-related behavior and synaptophysin immunoreactivity in the adult rat. On the other hand, MAP2 immunoreactivity was decreased by betamethasone in males, suggesting a permanent impairment in the hippocampus. Interestingly, the lower dose appears to have less influence in terms of growth restriction, known to be associated with an increased risk of disease in adulthood. Further research might elucidate whether the betamethasone effect on hippocampal neurons persists later in life and could affect the aging process increasing the risk for neuropathology of the adult.