Arteriovenous malformations (AVMs) are abnormal connections of vessels that shunt blood directly from arteries into veins. Rupture of brain AVMs (bAVMs) can cause life-threatening intracranial bleeding. Even though the majority of bAVM cases are sporadic without a family history, some cases are familial. Most of the familial cases of bAVMs are associated with a genetic disorder called hereditary hemorrhagic telangiectasia (HHT). The mechanism of bAVM formation is not fully understood. The most important advances in bAVM basic science research is the identification of somatic mutations of genes in RAS-MAPK pathways. However, the mechanisms by which mutations of these genes lead to AVM formation are largely unknown. In this review, we summarized the latest advance in bAVM studies and discussed some pathways that play important roles in bAVM pathogenesis. We also discussed the therapeutic implications of these pathways.

Tibia fracture (BF) enhances stroke injury and post-stroke memory dysfunction in mouse. Reduction of neuroinflammation by activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced acute neuronal injury and sensorimotor dysfunction in mice with BF 1-day after stroke. We hypothesize that reduction of neuroinflammation by activation of α-7 nAchR improves long-term memory function of mice with BF 6-h before stroke. The mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and methyllycaconitine (antagonist) treatment groups. The sensorimotor function was tested by adhesive removal and corner tests at 3 days, the memory function was tested by Y-maze test weekly for 8 weeks and novel objective recognition test at 8 weeks post-injuries. We found PHA-568487 treatment reduced, methyllycaconitine increased the number of CD68+ cells in the peri-infarct and hippocampal regions, neuronal injury in the infarct region, sensorimotor and long-term memory dysfunctions. PHA-568487 treatment also reduced, while methyllycaconitine treatment increased atrophy of hippocampal granule cell layer and white matter damage in the striatum. In addition, PHA-568487 treatment increased neuron proliferation in granule cell layer. Our data indicated that reduction of neuroinflammation through activation of α-7 nAchR decreased neuronal damage, sensorimotor and long-term memory dysfunction of mice with BF shortly before stroke.

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Background: Tibia fracture (BF) before stroke shortly causes long-term post-stroke memory dysfunction in mice. The mechanism is unclear. We hypothesize that BF enhances neuroinflammation and blood brain barrier (BBB) breakdown in the hippocampus and white matter (WM) damage. Methods: Mice were assigned to groups: BF, stroke, BF+stroke (BF 6 h before stroke) and sham. BBB integrity was analyzed 3 days after the surgeries and WM injury was analyzed 3 days and 8 weeks after the surgeries. Results: Stroke and BF+stroke groups had more activated microglia/macrophages and lower levels of claudin-5 in the ipsilateral hippocampi than the BF group. BF+stroke group had the highest number microglia/macrophages and the lowest level of claudin-5 among all groups and had fewer pericytes than BF group. Stroke and BF+stroke groups had smaller WM areas in the ipsilateral basal ganglia than the sham group 8 weeks after the injuries. The BF+stroke group also had smaller WM areas in the ipsilateral than sham and BF groups 3 days after the injuries and in the contralateral basal ganglia than stroke and BF groups 8 weeks after the injuries. Conclusions: BF exacerbates neuroinflammation and BBB leakage in the hippocampus and WM damage in basal ganglia, which could contribute to the long-lasting memory dysfunction in BF+stroke mice.