ABSTRACT
Alzheimer's disease (AD), the most common form of dementia, is characterized by neuronal degeneration and cerebrovascular dysfunction. Increasing evidence indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD. This emphasizes the importance to investigate the tight coupling between neuronal activity and cerebral blood flow (CBF) termed neurovascular coupling (NVC). NVC depends on all cell types of the neurovascular unit within which astrocytes are important players in the progression of AD. Hence, the objective of this study was to characterize the hippocampal NVC in a mouse model of AD. Hippocampal NVC was studied in 6-month-old amyloid-beta precursor protein (APP) transgenic mice and their corresponding wild-type littermates using in vivo laser Doppler flowmetry to measure CBF in area CA1 of the hippocampus in response to Schaffer collaterals stimulation. Ex vivo two-photon microscopy experiments were performed to determine astrocytic Ca2+ and vascular responses to electrical field stimulation (EFS) or caged Ca2+ photolysis in hippocampal slices. Neuronal synaptic transmission, astrocytic endfeet Ca2+ in correlation with reactive oxygen species (ROS), and vascular reactivity in the presence or absence of Tempol, a mimetic of superoxide dismutase, were further investigated using electrophysiological, caged Ca2+ photolysis or pharmacological approaches. Whisker stimulation evoked-CBF increases and ex vivo vascular responses to EFS were impaired in APP mice compared with their age-matched controls. APP mice were also characterized by decreased basal synaptic transmission, a shorter astrocytic Ca2+ increase, and altered vascular response to elevated perivascular K+. However, long-term potentiation, astrocytic Ca2+ amplitude in response to EFS, together with vascular responses to nitric oxide remained unchanged. Importantly, we found a significantly increased Ca2+ uncaging-induced ROS production in APP mice. Tempol prevented the vascular response impairment while normalizing astrocytic Ca2+ in APP mice. These findings suggest that NVC is altered at many levels in APP mice, at least in part through oxidative stress. This points out that therapies against AD should include an antioxidative component to protect the neurovascular unit.
ABSTRACT
INTRODUCTION: Opiates are traditionally used for treatment of some acute heart disorders. There are only few reports on the effects of long-term treatment of cardiovascular diseases with morphine. This study aimed to investigate the effects of chronic low-dose morphine use on the cardiovascular system in two-kidney one-clip (2K1C) hypertensive rats. MATERIALS AND METHODS: Male Wistar rats were divided into two groups as the sham and 2K1C groups and each group was further subdivided into saline and morphine treatment subgroups. Blood pressure, heart rate, plasma rennin activity, serum nitric oxide concentration, and baroreflex sensitivity were measured. RESULTS: Morphine significantly attenuated systolic blood pressure, diastolic blood pressure, and mean arterial pressure in the 2K1C animals. In addition, morphine decreased plasma rennin activity in the 2K1C group. Serum concentrations of nitric oxide were also decreased, and morphine prevented the reduction of nitric oxide. The baroreflex sensitivity was also improved following morphine administration in the 2K1C group. CONCLUSIONS: According to the results presented in this study, chronic administration of low-dose morphine reduces regulated hypertension in the 2K1C rats, probably via a nitric oxide-dependent pathway.
