Targeting the neurovascular unit for treatment of neurological disorders

Abstract

Drug discovery for CNS disorders has been restricted by the inability for therapeutic agents to cross the blood-brain barrier (BBB). Moreover, current drugs aim to correct neuron cell signaling, thereby neglecting pathophysiological changes affecting other cell types of the neurovascular unit (NVU). Components of the NVU (pericytes, microglia, astrocytes, and neurons, and basal lamina) act as an intricate network to maintain the neuronal homeostatic microenvironment. Consequently, disruptions to this intricate cell network lead to neuron malfunction and symptoms characteristic of CNS diseases. A lack of understanding in NVU signaling cascades may explain why current treatments for CNS diseases are not curative. Current therapies treat symptoms by maintaining neuron function. Refocusing drug discovery to sustain NVU function may provide a better method of treatment by promoting neuron survival. In this review, we will examine current therapeutics for common CNS diseases, describe the importance of the NVU in cerebral homeostasis and discuss new possible drug targets and technologies that aim to improve treatment and drug delivery to the diseased brain.

Figure 1

Figure 1a. Physiological NVU Cell Interactions. Neuron function is dependant upon a homeostatic microenvironment, which results from NVU cell-cell interactions. (A) Astrocytes interpret neuron signaling and modify release of factors in order to help maintain neuron metabolic needs. Astrocyte end feet have close contact with the cerebral endothelium, which helps to regulate blood flow and tight junction integrity. (B) Tight junctions are a unique phenotype to cerebral capillaries, which is distinctly differs from peripheral capillaries. Tight junctions provide an epithelial-like quality to the BBB, creating a physical and electrical barrier to prevent paracellular molecular passage. (C) Pericytes maintain basal lamina (not depicted) structure and may regulate blood flow. Evidence suggests the basal lamina is a point of contact for NVU intracellular communications. Proper structure is needed for sending and responding to cell-cell communications. (D) Microglia are cerebral monocytes that possess a stellate shape under physiological conditions. Physiological function of microglia within the NVU is not well defined. Figure 1b. Pathophysiological NVU Cell Interactions. Neuron distress signals are best characterized as inflammatory cytokines. Distress signals released from the neuron alter NVU function. (A) Astrocytes interpret distress signals, become activated and release inflammatory cytokines. This cascade may activate nearby astrocytes, depending on the degree of inflammation. (B) Signals released from the asctrocyte end feet lead to decreased tight junction integrity. These signals may result from enzyme release (e.g. MMP-9) leading to tight junction proteins degradation, a lack of tight junction protein forming factors, or a combination of both. (C) Pericyte ghosts have not been characterized in the CNS, but are commonly described in peripheral capillary dysfunction. Dysfunction or lack of pericytes leads to basal lamina thickening, which dysregulates NVU cell signaling and hemodynamics of cerebral blood flow. (D) Microglia respond to inflammatory signals, which result in mobility and ramified shape. These cerebral macrophages phagocytize debris, release cytotoxic factors, and propagate neuro-inflammation by releasing inflammatory cytokines. A balance between the stellate and ramified states is essential for maintaining cerebral homeostasis.

Figure 1

Figure 1a. Physiological NVU Cell Interactions. Neuron function is dependant upon a homeostatic microenvironment, which results from NVU cell-cell interactions. (A) Astrocytes interpret neuron signaling and modify release of factors in order to help maintain neuron metabolic needs. Astrocyte end feet have close contact with the cerebral endothelium, which helps to regulate blood flow and tight junction integrity. (B) Tight junctions are a unique phenotype to cerebral capillaries, which is distinctly differs from peripheral capillaries. Tight junctions provide an epithelial-like quality to the BBB, creating a physical and electrical barrier to prevent paracellular molecular passage. (C) Pericytes maintain basal lamina (not depicted) structure and may regulate blood flow. Evidence suggests the basal lamina is a point of contact for NVU intracellular communications. Proper structure is needed for sending and responding to cell-cell communications. (D) Microglia are cerebral monocytes that possess a stellate shape under physiological conditions. Physiological function of microglia within the NVU is not well defined. Figure 1b. Pathophysiological NVU Cell Interactions. Neuron distress signals are best characterized as inflammatory cytokines. Distress signals released from the neuron alter NVU function. (A) Astrocytes interpret distress signals, become activated and release inflammatory cytokines. This cascade may activate nearby astrocytes, depending on the degree of inflammation. (B) Signals released from the asctrocyte end feet lead to decreased tight junction integrity. These signals may result from enzyme release (e.g. MMP-9) leading to tight junction proteins degradation, a lack of tight junction protein forming factors, or a combination of both. (C) Pericyte ghosts have not been characterized in the CNS, but are commonly described in peripheral capillary dysfunction. Dysfunction or lack of pericytes leads to basal lamina thickening, which dysregulates NVU cell signaling and hemodynamics of cerebral blood flow. (D) Microglia respond to inflammatory signals, which result in mobility and ramified shape. These cerebral macrophages phagocytize debris, release cytotoxic factors, and propagate neuro-inflammation by releasing inflammatory cytokines. A balance between the stellate and ramified states is essential for maintaining cerebral homeostasis.

Figure 2

Metabolic and Physical Barrier Schematic of Adjacent Cerebral Endothelial Cells. The BBB possess both physical and metabolic mechanisms by which discrete microenvironments form within the brain to support optimal neuron function. (A) Efflux pumps (MDR, MRP, PGP) are present on the abluminal surface and actively extrude molecules from the endothelial cell, thereby preventing passage into the brain. (B) Metabolizing enzymes (MAO, CYP450s) are present on the abluminal surface and/or within the endothelial cell. These protein degrade harmful molecules and metabolize potential drug therapy, thereby preventing drug activity. (C) Tight junctions are cell-to-cell contacts consisting of transmembrane proteins (e.g. junction adhesion molecules, occludin, and claudin). Tight junctions create a physical barrier limiting paracellular passage and an electrical barrier to repel molecules from attempting BBB transport.

Figure 3

CNS Disease State Progression. Schematic depicts the relationship between NVU dysfunction and CNS disease progression. Further understanding of pathological NVU signaling will give incite to potential drug targets, inwhich will maintain the neuron microenvironment and neuron function.