Responses of crayfish neurons and glial cells to photodynamic impact: Intracellular signaling, ultrastructural changes, and neuroglial interactions

Photodynamic therapy (PDT), an inducer of oxidative stress, is used for treatment of cancer, including brain tumors. To study the mechanisms of photodynamic injury of neurons and glial cells (GC), we used a simple model object - isolated crayfish mechanoreceptor consisting of a single sensory neuron surrounded by a multilayered glial envelope. PDT caused inhibition and elimination of neuronal activity, impairment of intracellular organelles involved in the biosynthetic, bioenergetic, and transport processes and neuroglial interactions, necrosis of neurons and glial cells, and in glial apoptosis. PDT-induced death of a neuron and GC was mediated by intercellular molecular messengers and intracellular signaling cascades. PDT-induced inhibition and elimination of neuronal activity was associated with opening of mitochondrial permeability transition pores, Ca²⁺ release into cytosol, protein kinase C and NO synthase activities. Necrosis of neurons was mediated by protein kinases B/Akt, GSK-3β and mTOR, opening of mitochondrial permeability transition pores and Ca²⁺/calmodulin/ CaMKII pathway. NO and GDNF reduced neuronal necrosis. Multiple signal pathways, such as phospholipase C/Ca²⁺, Ca²⁺/calmodulin/CaMKII, Ca²⁺/PKC, Akt/mTOR, MEK/p38, and protein kinase G mediated PDT-induced necrosis both in glial cells and in neurons. NOS/NO and neurotrophic factors NGF and GDNF protected glial cells and demonstrated antinecrotic activity. Glial apoptosis was reduced by neurotrophic factors NGF and GDNF, protein kinase C, and MAP kinase JNK. In contrast, mitochondrial permeability transition pores and phospholipase C, which mobilize intracellular Ca ²⁺, NOS/NO/protein kinase G, proteins GSK-3β and mTOR, stimulated apoptosis of glial cells. The schemes of involvement of various inter- and intracellular signaling processes in the responses of neurons and GC to PDT are developed.