Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions

Abstract

Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study. Further, intensive antiplatelet therapy is known to be hazardous in small vessel disease through enhanced bleeding. Whether acetylcholinesterase inhibitors, which delay the progression of Alzheimer's dementia, are relevant in small vessel disease remains unclear. Potential prophylactic and treatment strategies might be those that target brain microvascular endothelium and the blood brain barrier, microvascular function and neuroinflammation. Potential interventions include endothelin antagonists, neurotrophins, nitric oxide donors and phosphodiesterase 5 inhibitors, peroxisome proliferator-activated receptor-gamma agonists, and prostacyclin mimics and phosphodiesterase 3 inhibitors. Several drugs that have relevant properties are licensed for other disorders, offering the possibility of drug repurposing. Others are in development. Since influencing multiple targets may be most effective, using multiple agents and/or those that have multiple effects may be preferable. We focus on potential small vessel disease mechanistic targets, summarize drugs that have relevant actions, and review data available from randomized trials on their actions and on the available evidence for their use in lacunar stroke.

Keywords: antithrombotics; blood brain barrier; blood pressure lowering; cyclic nucleotide inhibitors; nitric oxide; prostacyclin.

Figure 1

Venn diagram showing relationship between small vessel disease and other forms of stroke. The embedded neuroimages show, clockwise from the top: intracerebral haemorrhage (ICH), microbleeds, lacunes (‘lakes’ of cerebrospinal fluid), white matter hyperintensities (WMH), and an acute lacunar infarct (LACI). Percentages relate to SVD etiologies and complications and are approximate: ‘?’ indicates a lack of data.

Figure 2

Targets and potential pharmacological interventions for preventing and/or treating small vessel disease. The green arrows indicate the site of some actions of a drug. The diagram indicates drugs acting on red blood cells, platelets, endothelial cells, smooth muscle cells (and potentially on pericytes).