http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00231/full?
- 1Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Faculty of Medicine, Sede de Investigación Universitaria (SIU), University of Antioquia UdeA, Medellín, Colombia
- 2Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
Introduction
Neurological disorders are highly prevalent around the
globe. In 2008, neurodegenerative disorders were responsible for 1% of
disabilities worldwide (W.H.O., 2003).
Strokes account for 55% of all neurological diseases and are considered
the leading cause of permanent physical and mental disability (OMS, 2013).
The primary risk factors of stroke include hyperlipidemia,
hypertension, diabetes mellitus, and harmful habits, such as smoking and
excessive alcohol consumption. The high incidence of strokes is related
to an increased number of dementia cases and other emotional and
cognitive disorders, such as depression and memory loss (Ovbiagele and Nguyen-Huynh, 2011).
Death, physical deterioration, and altered quality of life are
consequences of the natural history of strokes among patients who
survive an ischemic event (Sacco, 1997, 1998; Feigin et al., 2003; Silva et al., 2006).
Interestingly, the coexistence of cerebral ischemia and
neurodegenerative pathologies profoundly impacts the development of
dementia, suggesting a reciprocal interaction between ischemia and
neurodegeneration (Nagy et al., 1997; Snowdon et al., 1997).
These observations, along with the results of epidemiological studies
that have indicated that Alzheimer’s disease (AD) and cerebrovascular
diseases share similar risk factors (Breteler, 2000), have shifted interest to vascular factors as fundamental contributors to the pathogenesis of neurodegenerative diseases (de la Torre and Mussivand, 1993; Kalaria, 2000; Iadecola and Gorelick, 2003).
This hypothesis has been supported by the experimental findings that
showed that amyloid-beta (Aβ) peptide, which is commonly detected in AD
patients, exhibits strong cerebrovascular effects and that
ischemia-induced responses to hypoxia are potent modulators of cerebral
amyloidogenesis (Iadecola, 2004).
Both Aβ peptide and vascular risk factors deteriorate the structure and
function of the neurovascular unit (NVU, consisting of the endothelium,
glia, neurons, pericytes, and the basal lamina) (Mirra and Gearing, 1997; Snowdon et al., 1997; Breteler, 2000; Kalaria, 2000; Iadecola and Gorelick, 2003; Iadecola, 2004).
The NVU acts as a guardian of cerebral homeostasis.
Neurons, glia, the perivascular space, and the endothelium are closely
interrelated to maintain the homeostasis of the brain microenvironment (Iadecola, 2010),
regulate blood flow, modulate the exchange across the blood-brain
barrier (BBB), contribute to immune vigilance and provide trophic
support to the brain (Iadecola, 2010).
Substantial evidence has shown that cerebrovascular dysfunction is
implicated in not only cognitive impairment (such as that of cognitive
origin) but also neurodegenerative diseases, such as AD (Chui et al., 1992; Alavi et al., 1998; Kalaria, 2000; Iadecola, 2004; Simpkins et al., 2005; Hachinski et al., 2006; Pendlebury et al., 2012).
Ischemic stroke is exacerbated by several risk factors that affect the
function and structure of blood vessels in the brain and cells
associated with the NVU, reducing the ability of the brain parenchyma to
repair due to the rupture of the BBB, the loss of brain blood flow
regulation, oxidative stress, inflammation, and the loss of neuronal
connections, ultimately increasing brain dysfunction (Deane et al., 2003; Ohab et al., 2006; Konsman et al., 2007; Weber et al., 2007; Bell et al., 2009; Wolburg et al., 2009).
The study of stroke has focused on understanding the molecular and
pathophysiological mechanisms of neuronal death, recovery and
pharmacological intervention strategies, as well as clinical and
epidemiological characteristics (Silva et al., 2006).
In addition, several molecular targets associated with endothelial
dysfunction and cardio-cerebrovascular risk, including CDK5, Rho
GTPases, and cell adhesion proteins, are described below and presented
in a hypothetical schematic in Figure 1 to explain and propose a potential neuroprotective approach for stroke.
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