Ginsenoside Re Rescues Methamphetamine-Induced Oxidative Damage, Mitochondrial Dysfunction, Microglial Activation, and Dopaminergic Degeneration by Inhibiting the Protein Kinase Cδ Gene

Abstract

Ginsenoside Re, one of the main constituents of Panax ginseng, possesses novel antioxidant and anti-inflammatory properties. However, the pharmacological mechanism of ginsenoside Re in dopaminergic degeneration remains elusive. We suggested that protein kinase C (PKC) δ mediates methamphetamine (MA)-induced dopaminergic toxicity. Treatment with ginsenoside Re significantly attenuated methamphetamine-induced dopaminergic degeneration in vivo by inhibiting impaired enzymatic antioxidant systems, mitochondrial oxidative stress, mitochondrial translocation of protein kinase Cδ, mitochondrial dysfunction, pro-inflammatory microglial activation, and apoptosis. These protective effects were comparable to those observed with genetic inhibition of PKCδ in PKCδ knockout (-/-) mice and with PKCδ antisense oligonucleotides, and ginsenoside Re did not provide any additional protective effects in the presence of PKCδ inhibition. Our results suggest that PKCδ is a critical target for ginsenoside Re-mediated protective activity in response to dopaminergic degeneration induced by MA.

Liposomal melatonin rescues methamphetamine‐elicited mitochondrial burdens, pro‐apoptosis, and dopaminergic degeneration through the inhibition PKCδ gene

“…Briefly, aliquots of 250 μ g of isolated mitochondrial protein were suspended in respiration buffer [250 m m sucrose, 20 m m HEPES, 2 m m MgCl 2 , 2.5 m m inorganic phosphates (pH 7.2), and 10 m m succinate (5 m m glutamate and 2.5 m m maleate gave similar results in all paradigms)] in a final volume of 200 μ L. The energized mitochondria were then incubated at 37° in the presence of 10 μ m JC‐1 for 30 min, after which fluorescence was measured with a fluorometric plate reader. The relative amount of mitochondrial polarization per milligram of mitochondria was quantified by taking the ratio of emission from 590 to 535 nm, respectively, with excitation at 500 nm .…”

“…A printout for each session showed the pattern of the ambulatory movements of the test box. The distance traveled in centimeter by the animals in horizontal locomotor activity was analyzed .…”

“…The test was performed 30 min after training and an accelerating paradigm was applied, starting from a rate of 4 rpm to maximal speed of 40 rpm, and then, the rotation speed was kept constant at 40 rpm. The latency to fall was measured with a maximal cutoff time of 300 s .…”

“…Earlier reports suggested that PKCδ is a functional tyrosine phosphorylation modulator of TH that plays a key role in apoptotic cell death of dopaminergic neurons . We have recently suggested that PKCδ mediates MA‐induced dopaminergic neurodegeneration by potentiating oxidative damage and inhibiting TH phosphorylation .…”

YY-1224, a terpene trilactone-strengthened Ginkgo biloba, attenuates neurodegenerative changes induced by β-amyloid (1-42) or double transgenic overexpression of APP and PS1 via inhibition of cyclooxygenase-2

“…This could lead to neuroinflammation and progression of neurodegeneration [76]. Microglia/macrophages are capable of undergoing phenotypic polarization to the M1 phenotype to produce pro-inflammatory cytokines, or to the M2 phenotype to produce anti-inflammatory cytokines [77, 78]. A prevalence of M1 over M2 microglia/macrophages has been reported in neurodegenerative pathologies, such as AD, and in the elderly brain [79].…”