Metabotropic glutamate receptors and nitric oxide in dopaminergic neurotoxicity

Figure 1 Proposed scheme for the involvement of nitric oxide and metabotropic glutamate receptor subtype 5 in rotenone-induced dopaminergic neurotoxicity. It is now generally accepted that rotenone in low doses of rotenone specifically binds complex I and induces mitochondrial dysfunction. The action of rotenone can be mediated by an increase in the N-methyl-D-aspartate current, which leads to the activation of metabotropic glutamate receptor subtype 5. Complex I, in combination with excitation of glutamate receptors, induces the generation of reactive oxygen species and nitric oxide. In summary, these key cellular events induce progressive death of dopaminergic neurons in the substantia nigra pars compacta via apoptosis and necrosis. It is important to note that at each stage, the action of rotenone becomes regionally limited so that inhibition of complex I ultimately lead to highly selective degeneration and loss of dopaminergic neurons of the nigrostriatal pathway. NO: Nitric oxide; ROS: Reactive oxygen species.