Amlodipine limits microglia activation and cognitive dysfunction in aged hypertensive mice
Danielle Kerkhofs1,2,3, Robin Helgers3, Denise Hermes4,5
1Department of Neurology, Maastricht University Medical Center.
Insights
Amlodipine, a calcium-channel blocker, improved short-term memory in aged hypertensive mice by reducing blood pressure variability and neuroinflammation. This suggests potential benefits against cognitive decline and cerebral small vessel disease.
Area of Science:
- Neuroscience
- Pharmacology
- Cardiovascular Medicine
Background:
- Cerebral small vessel disease, linked to stroke and dementia, is associated with systolic blood pressure (SBP) and blood pressure variability.
- Calcium-channel blockers can reduce blood pressure variability, potentially offering neuroprotection.
- The effects of calcium-channel blockers on hypertension-induced neuroinflammation and microglial phenotype are not well understood.
Purpose of the Study:
- To investigate the efficacy of amlodipine in mitigating microglia-associated inflammation.
- To assess the impact of amlodipine on cognitive dysfunction in aged hypertensive mice.
- To explore amlodipine's potential cerebroprotective effects beyond blood pressure reduction.
Main Methods:
- Amlodipine treatment (10 mg/kg/day) in hypertensive BPH/2J mice compared to untreated controls and normotensive BPN/3J mice.
- Blood pressure monitoring via telemetry and tail cuff plethysmography.
- Cognitive function assessment using memory tasks and brain immunohistochemistry for blood-brain barrier integrity and microglial activation (Iba1+CD68+ cells, morphology).
Main Results:
- Amlodipine normalized SBP and decreased blood pressure variability in hypertensive mice.
- Short-term memory impairment in BPH/2J mice was prevented by amlodipine.
- Amlodipine limited blood-brain barrier leakage size and partly reduced microglial inflammatory phenotype (increased Iba1+CD68+ cells, altered cell morphology).
Conclusions:
- Amlodipine attenuated short-term memory deficits in aged hypertensive mice.
- Beyond its antihypertensive effects, amlodipine demonstrates potential cerebroprotection by modulating neuroinflammation and microglial activation.
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 ± 0.25 in amlodipine-treated vs. 0.14 ± 0.15 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.
