Decades after identifying cannabinoids and their beneficial effects on Parkinson's disease (PD), many gaps are still missing. Although, CB2-dependent actions have been shown as underlying positive effects of cannabinoid treatment, in recent years, another receptor of cannabinoids, CB1, emerged as a valuable player in cannabinoid-induced neuroprotection. Remarkably, the effects of CB1 are mainly related to immune cells in the CNS, microglia, and astrocytes. However, oxidative stress, alpha-syn accumulation, and immune disbalance are essential aspects of both neurons and glial cells. Therefore, in this study, we investigated the effects of the CB1 on both alpha-syn and rotenone-treated SH-SY5Y and C8-D1A cells. ACEA and AM-251 were used as CB1 agonists and antagonists. Cell viability, IL-1 beta, IL-6, TNF-alpha levels, and CD200 expressions were determined in culture mediums. Our results demonstrated that preformed fibril form (pFF) of alpha-syn did not cause any significant change in SHSY5Y cells compared to C8-D1A cells. Rotenone significantly increased the expression of IL-1 beta, IL-6, and TNF-alpha levels in both cells. pFF alpha-syn and rotenone treatment caused a decrease in CD200 expression. Surprisingly both ACEA and AM-251 alleviated rotenone-induced increase in cytokine levels in both cell lines. Although ACEA prevented pFF alpha-syn induced increase in cytokine levels and decrease in CD200 expression in C8-D1A cells, AM251 failed to affect CD200 expression levels. Additionally, ACEA + AM-251 abolished the protective effects of both ACEA and AM-251 against rotenone and alpha-syn insults in both cell lines. The current study suggests that cannabinoid receptor agonism alleviates rotenone and alpha-syn-dependent inflammation in neurons and astrocytes.