Secondary degeneration may be mediated through several mechanisms. (i) Nitric oxide (NO) produced by macrophages and microglia may inhibit normal cellular respiration and mitochondrial ATP production. (ii) Reductions in neuronal ATP production may lead to failure of the Na⁺/K⁺ pump. The subsequent increases in intracellular concentrations of Na⁺ lead to reverse operation of the Na⁺/Ca²⁺ exchanger and opening of voltage-sensitive Ca²⁺ channels, resulting in a rise of intra-axonal Ca²⁺. (iii) This, in turn, may activate degradative enzymes, including proteases, phospholipases, and calpains, resulting in further neuronal or axonal damage and impaired ATP production. (iv) Microglia and macrophages recruited to the area produce glutamate, which can interact with NMDA or AMPA receptors, which also cause a rise in intracellular Ca²⁺. (v) Impaired glutamate uptake and degradation in the astrocyte, accompanied by downregulated expression of glutamine synthase (GS) and glutamate dehydrogenase (GDH), perpetuates increased extracellular glutamate levels. (vi) Astrocytes produce CCL2 and cytokines that further activate microglia and macrophages. In turn, microglia and macrophages consume damaged myelin sheaths and axons. (vii) Secondary neuronal cell body degradation can occur by apoptotic or necroptotic mechanisms, triggered in part by immune molecules (e.g., TNF-α, TRAIL) that are produced by microglia/macrophages or astrocytes.