PD is the second most prevalent neurodegenerative disorder affecting around 1% of adults over the age of 60. Regardless of the cause, oxidative stress and neuroinflammation play a vital role in the pathogenesis of neurodegeneration in PD. Furthermore, currently available medications can only alleviate symptoms but not prevent the pathological progression. As a result, finding neuroprotective drugs remains a top priority (Cacabelos, 2017). In brief, initial injury to dopaminergic cells caused by some factors including mitochondrial dysfunction, neurotoxins, and aging-related changes might be followed by elevated nigrostriatal RAS activation (Perez-Lloret et al., 2017). Furthermore, several studies had shown that the central RAS plays a role in the procces of neurodegeneration (Sathiya et al., 2013). Telmisartan which is AT1R blocker can cross the BBB and block brain AT1 receptors more effectively compared to other AT1 antagonists (Perez-Lloret et al., 2017) and was correlated with antioxidant and anti-inflammatory properties (Prathab Balaji et al., 2015). In neuronal culture, telmisartan was found to diminish the inflammatory response by blocking the c-Jun N-terminal kinase (JNK/c-Jun) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathways (Pang et al., 2012). According to previous studies, pro-inflammatory cytokines are higher in the cerebrospinal fluid and serum samples of PD patients, with post-mortem analysis revealing microglia and complement activation, as well as elevated pro-inflammatory cytokines in the striatum and SN (Hirsch and Hunot, 2009). Consequently, LPS model had been used in this study proving telmisartan's neuroprotective effects. LPS has been thoroughly characterised as a PD model due to its high ability to recapitulate several pathopysiological features of human PD such as dopaminergic neurodegeneration in the SN, microglia activation and motor deficits (Chen et al., 2017). In this research, telmisartan confirmed significant improvement in the LPS model of PD. The LPS lesioned rats produced a phenotypic behavior, fourteen days after LPS lesion initaition, the administration of subcutaneous apomorphine induced the increased number of rotations towards the lesioned side (Huang et al., 2018). This quantitative test has been performed to assess dopaminergic neuronal deficits and the treament efficacy (Abuirmeileh et al., 2008). Our results revealed that daily oral administration of telmisartan either before or after stereotaxic surgery has led to significant reductions in LPS induced- behavioral abnormalities. Similarly, Prathab Balaji et al. found experimentally that the treatment by telmisartan has demonstrated significant improvement in the behavioral activity (Prathab Balaji et al., 2015). Current results have established that telmisartan attenuated the depletion of dopamine amounts and significantly protected dopaminergic neurons from damage. This argument is supported by Tong et al. where telmisartan was reported to attenuate the accumulation of α-SYN in the SNpc and the depletion of dopamine in the striatum (Tong et al., 2016). Also, numerous recent studies have shown that telmisartan inhibits dopaminergic cell loss and the microglial inflammatory response in PD animal models through the activation peroxisome proliferator-activated receptor gamma (PPAR-γ) and by the direct antagonist action on AT1 receptors (Garrido-Gil et al., 2012).
A growing evidence confirms that central RAS has been involved in the pathogenesis and progression of PD (Tong et al., 2016). A local RAS has been found in several brain regions, involving the dopaminergic system and the basal ganglia (Perez-Lloret et al., 2017). The depletion of DA cells resulted from DA neurotoxins is known to be exacerbated by angiotensin II (AII) through AT1 receptors, which activate the superoxide production and NADPH complex. It had been observed that the activation of microglial NADPH complex and the inflammatory response mediator such as TNF-α via AT1 play a major role in PD (Villar-Cheda et al., 2010). Building on this conclusion, our results demonstrated that telmisartan either 3 days before LPS lesioning or 7 days after LPS lesioning significantly decreased the high levels of TNF-α. Similary, Elkahloun et al. had found that telmisartan significantly decreased the expression of the pro-inflammatory cytokine TNF-α that was activated by LPS, which reinforces the hypothesis that telmisartan could play an essential role in preventing or delaying neurodegenerative and age-related disorders (Elkahloun et al., 2019). Microglia play an active role in the progression of pathological neuroinflammatory process through releasing the proinflammatory cytokines, which contribute to the toxicity of neurons. One of the most important factors in inflammatory activation is nuclear factor-kappa B, a transcription factor that promotes the expression of multiple pro and antiapoptotic genes, involving BDNF (Lima Giacobbo et al., 2019). Miwa et al. found that the activated microglia by LPS caused a marked increase of BDNF (Miwa et al., 1997). Moreover, according to some reports, BDNF levels are elevated in PD patients, especially in the moderate to severe stages. This might mean that the CNS attempts to cope with the loss of dopaminergic neurons by increasing BDNF production, resulting in higher serum levels of the protein (Lima Giacobbo et al., 2019). In this study, our results demonstrated that telmisartan either 3 days before LPS lesioning or 7 days after LPS lesioning significantly reduced the levels of BDNF in LPS group. Referring to our previous argument and during neuroinflammation, when microglia cells are activated, they produce neurotoxic molecules and neurotrophic factors based on their pro-inflammatory M1 and anti-inflammatory M2 phenotypes. Activation of the M1 phenotype increases oxidative stress-induced products, promotes neuroinflammation, and increases neuronal damage. In contrast, activation of the M2 phenotype enhances the production of the anti-inflammatory factors, leading to reducing neuronal injury and neuroinflammation (Xu et al., 2015). In summary, our data displays the beneficial effects of telmisartan neuroprotective properties against the lesion induced by LPS through preserving striatal levels of dopamine, reducing TNF-α and BDNF concentrations, thus, telmisartan appears to be a promising agent for PD prevention and possible treatment.