Advances in astrocyte-targeted approaches for stroke therapy: an emerging role for mitochondria and microRNAS

Abstract

Astrocytes are critical regulators of neuronal function and an effective target for stroke therapy in animal models. Identifying individual targets with the potential for simultaneous activation of multiple downstream pathways that regulate astrocyte homeostasis may be a necessary element for successful clinical translation. Mitochondria and microRNAs each represent individual targets with multi-modal therapeutic potential. Mitochondria regulate metabolism and apoptosis, while microRNAs have the capacity to bind and inhibit numerous mRNAs. By combining strategies targeted at maintaining astrocyte function during and following cerebral ischemia, a synergistic therapeutic effect may be achieved.

Figure 1

Astrocyte-targeted therapies can elicit multiple mechanisms of neuroprotection. ROS = reactive oxygen species.

Figure 2

Mechanisms for mitigating cell death include targeting endogenous regulators of mitochondrial homeostasis and intracellular Ca²⁺ handling, HSP75, GRP78 and BCL2. When mitochondrial matrix Ca²⁺ exceeds buffering capacity mitochondrial function becomes impaired and results in opening of the mitochondrial permeability transition pore releasing cytochrome c and other pro-apoptotic factors into the cytoplasm. With energy depletion, increased free cytosolic Ca²⁺ is transmitted to the matrix of mitochondria by voltage-dependent anion channels (VDACs) on the outer mitochondrial membrane (OMM) and the mitochondrial Ca²⁺ uniporter (MCU) located on the inner mitochondrial membrane (IMM). Direct transfer of Ca²⁺ from the endoplasmic reticulum (ER) to mitochondria can also occur via the mitochondrial-associated membrane (MAM) complex, formed by the ER inositol 1,4,5-trisphosphate receptor (IP3R), mitochondrial VDACs, and other proteins. HSP75 modulates the activity of MAM while GRP78 serves to mitigate Ca²⁺ release from the ER to cytosol. BCL2 coordinates both mitochondrial function and induction of apoptosis.

Figure 3

Effective astrocyte-targeted strategies for inducing neuroprotection vary in complexity. “Upstream” strategies, such as increasing or decreasing endogenous miRs to improve astrocytic mitochondrial homeostasis, target a greater number of mechanisms and may have a greater downstream effect on overall cellular homeostasis and neuroprotection. BCL2 = B cell lymphoma 2; BDNF = brain derived neurotrophic factor; GLT-1 = glutamate transporter 1; GRP78 = glucose regulated protein 78 (BiP); HSP72 = heat shock protein 72; HSP75 = heat shock protein 75 (GRP75 glucose regulated protein 75 also known as mortalin); MCL1 = Myeloid cell leukemia 1; PUMA = p53 upregulated modulator of apoptosis.ROS = reactive oxygen species; XIAP = X-linked inhibitor of apoptosis.