Delayed Minocycline Treatment Ameliorates Hydrocephalus Development and Choroid Plexus Inflammation in Spontaneously Hypertensive Rats

Abstract

Hydrocephalus is a complicated disorder that affects both adult and pediatric populations. The mechanism of hydrocephalus development, especially when there is no mass lesion present causing an obstructive, is poorly understood. Prior studies have demonstrated that spontaneously hypertensive rats (SHRs) develop hydrocephalus by week 7, which was attenuated with minocycline. The aim of this study was to determine sex differences in hydrocephalus development and to examine the effect of minocycline administration after hydrocephalus onset. Male and female Wistar–Kyoto rats (WKYs) and SHRs underwent magnetic resonance imaging at weeks 7 and 9 to determine ventricular volume. Choroid plexus epiplexus cell activation, cognitive deficits, white matter atrophy, and hippocampal neuronal loss were examined at week 9. In the second phase of the experiment, male SHRs (7 weeks old) were treated with either saline or minocycline (20 mg/kg) for 14 days, and similar radiologic, histologic, and behavior tests were performed. Hydrocephalus was present at week 7 and increased at week 9 in both male and female SHRs, which was associated with greater epiplexus cell activation than WKYs. Male SHRs had greater ventricular volume and epiplexus cell activation compared to female SHRs. Minocycline administration improved cognitive function, white matter atrophy, and hippocampal neuronal cell loss. In conclusion, while both male and female SHRs developed hydrocephalus and epiplexus cell activation by week 9, it was more severe in males. Delayed minocycline treatment alleviated hydrocephalus, epiplexus macrophage activation, brain pathology, and cognitive impairment in male SHRs.

DPA714 PET Imaging Shows That Inflammation of the Choroid Plexus Is Active in Chronic-Phase Intracerebral Hemorrhage

“…However, the therapeutic strategies for prevention and treatment are lacking in hydrocephalus 5 . Inhibiting acute-phase CP inflammation can reduce the degree of hydrocephalus in animal experiments by minocycline (a microglia/macrophage inhibitor) or clodronate liposomes (a macrophage depleting agent) 9,11,13 . To further investigate whether chronic-phase ICH can also be treated by ameliorating CP inflammation to attenuate VE, we used in vivo TSPO-targeting 18 F-DPA714 PET to provide evidence supporting continued CP inflammation in chronic-phase ICH patients as the difficulty to obtain CP samples from patients with ICH.…”

“…5 Inhibiting acute-phase CP inflammation can reduce the degree of hydrocephalus in animal experiments by minocycline (a microglia/macrophage inhibitor) or clodronate liposomes (a macrophage depleting agent). 9,11,13 To further investigate whether chronic-phase ICH can also be treated by ameliorating CP inflammation to attenuate VE, we used in vivo TSPO-targeting 18 F-DPA714 PET to provide evidence supporting continued CP inflammation in chronic-phase ICH patients as the difficulty to obtain CP samples from patients with ICH. The clinical data showed that CP inflammation persists in chronic-phase ICH patients, which fills the gap in the field of CP inflammation after ICH in the chronic phase, and there was also a moderate positive correlation between VE and CP DPA714 uptake.…”

Altered Expression of AQP1 and AQP4 in Brain Barriers and Cerebrospinal Fluid May Affect Cerebral Water Balance during Chronic Hypertension

“…It has been described as progressive ventricular dilatation in SHR between 4 and 8 weeks of age compared to the control WKY rat, but the mechanisms underlying hydrocephalus in SHRs are still uncertain [ 17 , 18 , 19 , 20 ]. Recent studies revealed that both male and female SHRs had hydrocephalus at week 7, which got worse at week 9 and was more severe in males [ 21 , 22 ]. Changes in CSF homeostasis have been heavily associated with the pathophysiology of hydrocephalus [ 22 , 23 ].…”

“…Recent studies revealed that both male and female SHRs had hydrocephalus at week 7, which got worse at week 9 and was more severe in males [ 21 , 22 ]. Changes in CSF homeostasis have been heavily associated with the pathophysiology of hydrocephalus [ 22 , 23 ]. Alterations in AQPs expression may contribute to hydrocephalus due to impaired water reabsorption in the venous compartment [ 24 , 25 , 26 ].…”

Molecular Mechanisms of Cerebrovascular Diseases

“…Hypertension also has effects on neuroinflammation. Hao et al [8] reported hydrocephalus development in the spontaneously hypertensive rat (SHR) compared with the parent Wistar Kyoto rat strain. This was associated with inflammation at the choroid plexus (the blood-CSF barrier) and treating SHRs with minocycline reduced hydrocephalus and choroid plexus inflammation as well as improved cognitive function, white matter atrophy, and hippocampal neuronal cell loss.…”