Therapy Opportunities and Strategies Brain Revascularization in Stroke, Neurodegeneration, and Aging

Summary

Central nervous system (CNS) diseases, especially acute ischemic events and neurodegenerative disorders, constitute a public health problem with no effective treatments to allow a persistent solution. Failed therapies targeting neuronal recovery have revealed the multifactorial and intricate pathophysiology underlying such CNS disorders as ischemic stroke, Alzheimer's disease, amyotrophic lateral sclerosis, vascular Parkinsonism, vascular dementia, and aging, in which cerebral microvasculature impairment seems to play a key role. 

In fact, a reduction in vessel density and cerebral blood flow occurs in these scenarios, contributing to neuronal dysfunction and leading to loss of cognitive function. In this review, we provide an overview of the structure and function of healthy cerebral microvasculature and the effect of the aforementioned brain diseases. We discuss new emerging therapeutic opportunities and their delivery approaches, aimed at recovering brain vascularization in this context. 

Speaking statement The absence of effective treatments, mainly focused on the recovery of neurons, caused the search for other therapies to treat brain diseases in the central nervous system. The disturbance and degeneration of cerebral microvasculature have been highlighted in neurodegenerative diseases, brain vascular accidents, and aging, constituting a potential target to restore vascularization, neuronal functioning, and cognitive capacities through the development of therapeutic strategies proangiogenic strategies.

Introduction

Neurologic disorders are the second leading cause of death and the principal cause of disability in the world (GBD 2015 Neurologic Disorders Collaborator Group, 2017). The whole life expectancy and population growth in the world imply that more and more people reach ages in which neurological disorders are more widespread. 

The increasing incidence and prevalence of these diseases linked to the central nervous system (SNC) have a significant socioeconomic impact, so this becomes a real problem not only for patients and families but also for the economy and care systems health (Harper, 2014; Wimo et al., 2020). There are no curative pharmacological treatments capable of achieving complete neurovascular recovery in SNC diseases; They can only slow down neurological degenerative processes. 

This scenario underscores the difficulty of current pharmacological drugs to target and efficiently act in the brain. One of the main obstacles that lack the success of such therapies is the blood-brain-barrier (BBB), along with other factors that must be taken into consideration, such as the presence of other extracellular and intracellular barriers and the complexity of the neurovascular network with interactions at several levels. 

For this reason, huge research efforts are being conducted to find and develop novel therapeutic strategies for CNS diseases (Niu et al., 2019; Poovaiah et al., 2018; Teleanu et al., 2019). A few years ago, neuroscientists considered the brain as a dichotomized organ comprised of brain cells and cerebral blood vessels, with no relationship between these two entities. Nowadays, however, the scientific community is aware of the close connection established and required between neuronal and vascular CNS cells for correct brain functioning. 

The brain is one of the most infused organs of the body; In fact, almost all neurons have their own capillary (Zlokovic, 2005), highlighting the pivot relationship between neural and vascular systems, called the neurovascular network. 

The neurovascular network of the SNC is responsible for the supply of 20% of the cardiac output carrying oxygen and brain nutrients (Iadecola, 2013) and thus contributing to a healthy neurological function. This is why the absence of this supply, caused by damage or degeneration of vessels, could have a major role in the pathogenesis of SNC diseases. 

Consequently, it is not surprising that cognitive disorders that occur in many SNC diseases can be linked to cerebrovascular disturbances, mainly in terms of micro vascularization, and to reducing brain blood flow, as in the case of 'Ischemic stroke, amyotrophic lateral sclerosis (ALS), Alzheimer disease RS (AD), vascular parkinsonism (VP), vascular dementia (VAD) and aging, which will be described in depth in section III, vascular disorders in diseases of the diseases of Brain SNC. 

This review gives an overview of the cellular and molecular mechanisms necessary to manage cerebral micro vascularization, as well as -to -an date perspective of SNC diseases related to damage or deterioration of cerebral micro vascularization, as is the case for a stroke Ischemic, an Alzheimer RS (AD) disease, amyotrophic lateral sclerosis (SLA), vascular parkinsonism (VP), vascular dementia (VAD) and aging, which are all associated with cognitive disorders.

In particular, we describe evidence of the regeneration of micro vascularization as a form of improvement in neurological and cognitive functions by examining the progress of the identification of potential therapeutic pro-angiogenic factors and focusing on nanotechnological approaches, opportunities advanced and administration strategies used.

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