Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

Abstract

Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.Acta Pharmacologica Sinica (2009) 30: 879-888; doi: 10.1038/aps.2009.82.

Figure 1

Pathways of ischemic vascular cognitive impairment/dementia and possible therapeutic approaches. Following cerebral ischemia, energy failure and subsequent events including inflammation, glutamate-mediated excitotoxicity, calcium overload, initiation of intracellular death pathways, oxidative stress, and structural and functional changes occur. Mediators of these events interact with each other and contribute to cellular damage, in which a cholinergic deficit is involved, and finally cause cognitive impairment or dementia. Current neuroprotective treatment options cover all of the molecular targets of the dementia cascades. Interestingly, protective effects of cholinergic agents, especially AChE inhibitors, involve multiple mechanisms (I^{, , ,} ; II^{, ,} ; III^, ; IV^, ; V^{, ,} ; references to literature regarding VI and VII can be found throughout this review). Abbreviations: ATP, adenosine triphosphate; CaM, calmodulin; Hup A, huperzine A; JAK/STAT, Janus kinase/signal transducer and activator of transcription; MMP, matrix metalloproteinase; NGF, nerve growth factor; NMDA, N-methyl-D-aspartic acid; PAF, platelet activating factor.