ALS and oxidative stress: the neurovascular scenario

Abstract

Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS.

Figures

Figure 1

The role of hypoxia in stimulating the VEGF through an activation of HIF-1 alpha element. HIF-1 alpha gets activated in deficiency of oxygen in mitochondria leading to creation of oxidative stress. This involves the formation of reactive oxygen species which on reaction with free nitrogen forms NO ultimately leading to reactive nitrogen species (RNS). This RNS further activates NF-κB pathway which ultimately leads to activation of HIF-1 alpha factor. The activated form of HIF-1 alpha further leads to VEGF activation thus leading to angiogenesis.

Figure 2

Role of hypoperfusion in elevation of oxidative stress and energy failure. As hypoperfusion reduces blood flow towards cells resulting in reduced ferritin Fe3+ protein, it releases unbound iron Fe2+ molecules resulting in formation of ROS thus increasing the oxidative stress. Hypoperfusion also leads to unavailability of glucose to brain cells thus leading to energy failure.

Figure 3

Hypoxia induced mobilisation of astrocytes. Astrogliosis is the result of aggressive increase of astrocytes number in the vicinity of damaged neuron cell. Synapse formation is hampered when there is neuronal damage thus leading to breakdown of Na+K+ homeostasis. This K+ concentration is detected by the astrocytes.

Figure 4

VEGF and permeability of blood brain barrier. Astrocytic expression of HIF-alpha and VEGFA leads to downregulation of claudins CLN-5 and their regulatory protein OCLN. VEGFA, by the virtue of tyrosine phosphorylation, downregulates the expression of CLN ultimately resulting in disruption of permeability barrier. VEGF induces the migration among the endothelial cells and increases the permeability to CNS.