Clonidine and Brain Mitochondrial Energy Metabolism: Pharmacodynamic Insights Beyond Receptorial Effects

Clonidine is an anti-hypertensive drug that inhibits the release of norepinephrine from pre-synaptic terminals binding to pre-synaptic α₂-adrenoreceptors. Some studies suggest that this drug decreases brain energy expenditure, particularly in hypoxic-ischemic injury. However, data about clonidine effects on the functional parameters regulating brain energy metabolism are lacking. In this study, the effects of acute clonidine treatment (5 μg×kg^-1 i.p., 30 min) were evaluated on the catalytic activity of regulatory energy-linked enzymes of Krebs' cycle, Electron Transport Chain and glutamate metabolism of temporal cerebral cortex of 3-month-old male Sprague-Dawley rats. Enzyme activities were assayed on non-synaptic "free" mitochondria (FM) of neuronal perikaryon and partly of glial cells, and on intra-synaptic "light" (LM) and "heavy" mitochondria (HM), localized within synaptic terminals. This subcellular analysis differentiates clonidine effects on post-synaptic and pre-synaptic neuronal compartments. The results showed that clonidine increased citrate synthase, cytochrome oxidase and glutamate-oxaloacetate transaminase activities of FM. In LM, citrate synthase activity was decreased, while cytochrome oxidase and glutamate-oxaloacetate transaminase activities were increased; on the contrary, citrate synthase, cytochrome oxidase and glutamate dehydrogenase were all decreased in HM. Therefore, clonidine exerted different effects with respect to brain mitochondria, coherently with the in vivo energy requirements of each synaptic compartment: the drug increased energy-linked enzyme activities in post-synaptic compartment, while the metabolic variations were complex in the pre-synaptic one, being enzyme activities heterogeneously modified in LM and decreased in HM. This study highlights the relationships existing between the clonidine-induced neuroreceptorial effects and the energy metabolism in pre- and post- synaptic bioenergetics.