Many investigators believe that primary neuronal dysfunction resulting from an intrinsic neuronal disorder is the key underlying event in human neurodegenerative diseases. Thus, most therapeutic efforts for neurodegenerative diseases have so far been directed at the development of so-called ‘single-target, single-action’ agents to target neuronal cells directly and reverse neuronal dysfunction and/or protect neurons from injurious insults. However, most preclinical and clinical studies have shown that such drugs are unable to cure or control human neurological disorders2,181,183,194,195
. For example, although pathological overstimulation of glutaminergic NMDA receptors (NMDARs) has been shown to lead to neuronal injury and death in several disorders, includ- ing stroke, Alzheimer’s disease, ALS and Huntington’s disease16
, NMDAR antagonists have failed to show a therapeutic benefit in the above-mentioned human neurological disorders.
Recently, my colleagues and I coined the term vascul-oneuronal-inflammatory triad195
to indicate that vascular damage, neuronal injury and/or neurodegeneration, and neuroinflammation comprise a common pathological triad that occurs in multiple neurological disorders. In line with this idea, it is conceivable that ‘multiple-target, multiple-action’ agents (that is, drugs that have more than one target and thus have more than one action) will have a better chance of controlling the complex disease mechanisms that mediate neurodegeneration than agents that have only one target (for example, neurons). According to the vasculo-neuronal-inflammatory triad model, in addition to neurons, brain endothelium, VSMCs, pericytes, astrocytes and activated microglia are all important therapeutic targets.
Here, I will briefly discuss a few therapeutic strategies based on the vasculo-neuronal-inflammatory triad model. VEGF and other angioneurins may have multiple targets, and thus multiple actions, in the CNS120
. For example, preclinical studies have shown that treatment of SOD1G93A
rats with intracerebroventricular VEGF196
or intramuscular administration of a VEGF-expressing lentiviral vector that is transported retrogradely to motor neurons in SOD1G93A
reduced pathology and extended survival, probably by promoting angiogenesis and increasing the blood flow through the spinal cord as well as through direct neuronal protective effects of VEGF on motor neurons. On the basis of these and other studies, a phase I–II clinical trial has been initiated to evaluate the safety of intracerebroventricular infusion of VEGF in patients with ALS198
. Treatment with angiogenin also slowed down disease progression in a mouse model of ALS199
delivery has been shown to promote amyloid-β vascular clearance and to improve learning and memory in a mouse model of Alzheimer’s disease200
. Local intracerebral implantation of VEGF-secreting cells in a mouse model of Alzheimer’s disease has been shown to enhance vascular repair, reduce amyloid burden and improve learning and memory201
. In contrast to VEGF, which can increase BBB permeability, TGFβ, hepatocyte growth factor and fibroblast growth factor 2 promote BBB integrity by upregulating the expression of endothelial junction proteins121
in a similar way to APC43
. However, VEGF and most growth factors do not cross the BBB, so the development of delivery strategies such as Trojan horses is required for their systemic use25
A recent experimental approach with APC provides an example of a neurovascular medicine that has been shown to favorably regulate multiple pathways in non- neuronal cells and neurons, resulting in vasculo-protection, stabilization of the BBB, neuroprotection and anti-inflammation in several acute and chronic models of the CNS disorders195
Box 2. A model of multiple-target, multiple-action neurovascular medicine
Activated protein C (APC) is an endogenous plasma protease with antithrombotic, cytoprotective and anti-inflammatory activities in the CNS195
. APC and recombinant analogues of this protease that have been engineered to have reduced or no anticoagulant activity have excellent therapeutic potential as disease-modifying therapies for neuropathologies that are driven by the vasculo-neuronal-inflammatory triad and, hence, involve vascular damage with blood–brain barrier (BBB) or blood–spinal cord barrier (BSCB) breakdown, neuronal injury and/or neurodegeneration, and neuroinflammation. Although much remains to be learned with respect to the biology of APC, APC-mediated signaling within the injured neurovascular unit (NVU) has beneficial effects in experimental models of amyotrophic lateral sclerosis (ALS)43
, multiple sclerosis212
, multiple models of stroke, spinal cord injury and brain trauma195
. Here, drawing on data from a transgenic SOD1G93A mouse model of ALS, the multiple effects of APC on different cell types within the NVU in the spinal cord are shown43
. APC protects brain endothelium from divergent inducers of apoptosis by first binding to the endothelial protein C receptor (EPCR). Activation of this receptor is required for activation of proteinase-activated receptor 1 (PAR1), which in turn induces cell protective signaling in the endothelium. PAR1 also cross-activates sphigosine 1 phosphate receptor 1 (S1P1), which enhances the integrity of endothelial barrier and inhibits BSCB breakdown195
. APC’s action contributes to vascular repair of the NVU by ameliorating red blood cell extravasation, causing microhaemorrhages and inducing accumulation of neurotoxic reactive oxygen species in the spinal cord. EPCR also mediates transcytosis of APC across the BBB28
. Once in the spinal cord interstitial fluid (ISF), APC reaches motor neurons and exerts its direct neuronal protective activity by blocking the apoptotic pathways that are induced by divergent injurious stimuli, and by downregulating mutant superoxide dismutase 1 (mSOD1) expression. The effect of APC on neurons is mediated by PAR1 and PAR3 receptors. APC exerts its anti-inflammatory activity by activating PAR1 in microglia, which suppresses the activation of these cells and, therefore, inhibits the expression of inflammatory cytokines. PAR1 activation by APC also inhibits mSOD1 expression in microglia.
A model of multiple-target, multiple-action neurovascular medicine
The recognition of amyloid-β clearance pathways (), as discussed above, opens exciting new therapeutic opportunities for Alzheimer’s disease. Amyloid-β clearance pathways are promising therapeutic targets for the future development of neurovascular medicines because it has been shown both in animal models of Alzheimer’s disease1 and in patients with sporadic Alzheimer’s disease149
that faulty clearance from brain and across the BBB primarily determines amyloid-β retention in brain, causing the formation of neurotoxic amyloid-β oligomers56
and the promotion of brain and cerebrovascular amyloidosis3. The targeting of clearance mechanisms might also be beneficial in other diseases; for example, the clearance of extracellular mutant SOD1 in familial ALS, the prion protein in prion disorders and α-synuclein in Parkinson’s disease might all prove beneficial. However, the clearance mechanisms for these proteins in these diseases are not yet understood.