Lycopodium Attenuates Loss of Dopaminergic Neurons by Suppressing Oxidative Stress and Neuroinflammation in a Rat Model of Parkinson’s Disease

Abstract

Parkinson’s disease, a chronic, age related neurodegenerative disorder, is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Several studies have proven that the activation of glial cells, presence of alpha-synuclein aggregates, and oxidative stress, fuels neurodegeneration, and currently there is no definitive treatment for PD. In this study, a rotenone-induced rat model of PD was used to understand the neuroprotective potential of Lycopodium (Lyc), a commonly-used potent herbal medicine. Immunohistochemcial data showed that rotenone injections significantly increased the loss of dopaminergic neurons in the substantia nigra, and decreased the striatal expression of tyrosine hydroxylase. Further, rotenone administration activated microglia and astroglia, which in turn upregulated the expression of α-synuclein, pro-inflammatory, and oxidative stress factors, resulting in PD pathology. However, rotenone-injected rats that were orally treated with lycopodium (50 mg/kg) were protected against dopaminergic neuronal loss by diminishing the expression of matrix metalloproteinase-3 (MMP-3) and MMP-9, as well as reduced activation of microglia and astrocytes. This neuroprotective mechanism not only involves reduction in pro-inflammatory response and α-synuclein expression, but also synergistically enhanced antioxidant defense system by virtue of the drug’s multimodal action. These findings suggest that Lyc has the potential to be further developed as a therapeutic candidate for PD.

Neuroprotective Effects of Pomegranate Juice against Parkinson’s Disease and Presence of Ellagitannins-Derived Metabolite—Urolithin A—In the Brain

“…H&E staining revealed degenerative and necrotic changes in the form of shrunken neurons with dark cytoplasm and pyknotic nuclei. The neurodegeneration was reflected by the loss of TH-positive cells in the SN region, which is in line with previous studies [41,42]. The administration of pomegranate juice to rotenone-intoxicated rats ameliorated the damaging effect of the neurotoxin since only some neurons with dark cytoplasm were still observed in the SN region and enhanced survival of TH+ neurons in this area was noticed.…”

“…Therefore, we assessed the effects of pomegranate juice treatment on the antioxidant defense system in the midbrain. Although many authors have shown the decrease in GSH level and/or antioxidant enzymes activity in this brain area of rats exposed to rotenone [31,[40][41][42][47][48][49][50], in our experiment, these markers were not affected significantly by rotenone administration. Differences in the response can be associated with the higher doses of rotenone, ranging between 1.5 mg/kg b.w.…”

“…It seems that PJ caused down-regulation of α-synuclein protein expression since in rats treated alone with the juice, the levels of α-synuclein oligomers was decreased while the ratio of this fraction to monomeric was higher than in Control. This effect is likely to be involved in the improvement of neuronal cell survival, which was also reported for other natural preparations [42,62].…”

“…Differences in the response can be associated with the higher doses of rotenone, ranging between 1.5 mg/kg b.w. and 2.5 mg/kg b.w., and a route of its administration, which was mainly intraperitoneal [39][40][41][42]. Manjunath and Muralidhara [51] have used lower rotenone dose, i.e., 1 mg/kg b.w., and noticed no significant change either in SOD or in GPx activity in the striatum of rats.…”

“…We did not find any significant difference in inflammatory response among the groups, but it might be related to the moderate level of rotenone-induced lipid peroxidation. Several authors have reported an increased expression of proinflammatory cytokines, including TNF-α and/or level of total NO accompanied by very high (3-5-fold) increase in MDA level in the midbrain of animals administered with rotenone [42,50,57].…”