International Journal of Molecular Sciences Review Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson’s Disease Giovanni Schepici, Serena Silvestro, Placido Bramanti and Emanuela Mazzon * IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy; [email protected] (G.S.); [email protected] (S.S.); [email protected] (P.B.) * Correspondence: [email protected]; Tel.: +39-090-60128172 Received: 30 May 2020; Accepted: 3 July 2020; Published: 4 July 2020 Abstract: Parkinson’s Disease (PD) is a neurological disease characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway with consequent loss of neurons in the substantia nigra pars compacta and dopamine depletion. The cytoplasmic inclusions of α-synuclein (α-Syn), known as Lewy bodies, are the cytologic hallmark of PD. The presence of α-Syn aggregates causes mitochondrial degeneration, responsible for the increase in oxidative stress and consequent neurodegeneration. PD is a progressive disease that shows a complicated pathogenesis. The current therapies are used to alleviate the symptoms of the disease without changing its clinical course. Recently, phytocompounds with neuroprotective effects and antioxidant properties such as caffeine have aroused the interest of researchers. The purpose of this review is to summarize the preclinical studies present in the literature and clinical trials recorded in ClinicalTrial.gov, aimed at illustrating the effects of caffeine used as a nutraceutical compound combined with the current PD therapies. Therefore, the preventive effects of caffeine in the neurodegeneration of dopaminergic neurons encourage the use of this alkaloid as a supplement to reduce the progress of the PD. Keywords: caffeine; Parkinson’s Disease; experimental models; neuroprotective effects; clinical trials 1. Introduction PD is a neurodegenerative disorder characterized by the progressive neurodegeneration of the dopaminergic neurons in the substantia nigra pars compacta and in the corpus striatum [1]. The presence of α-Syn protein aggregates in neuronal cells, known as Lewy bodies, is a pathological hallmark of PD [2]. Clinically, PD is characterized by several symptoms such as tremors, postural instability, muscle stiffness, bradykinesia and akinesia. Moreover, the disease is supported by cognitive decline, anxiety, recurrent visual hallucinations, sleep disturbances, dementia and psychosis [3]. The etiopathogenesis of PD is multifactorial; indeed, genetic mutations and environmental factors are involved in the onset of the disease. The familial forms of PD are caused by autosomal dominant and recessive mutations in several genes such as α-Syn (SNCA), ubiquitin C-terminal hydrolase L1 (UCHL-1), phosphatase and tensin homolog-induced putative kinase 1 (PINK1), PARKIN (PRKN), protein deglycase (DJ-1) and leucine-rich repeat kinase 2 (LRRK2)[4]. Environmental factors such as exposure to herbicides; heavy metals; and pesticides including rotenone (ROT), dichlorodiphenyltrichloroethane, paraquat (PQ) and maneb (MB) are risk factors for the onset of idiopathic forms of PD [5]. To date, PD treatment involves the use of drugs capable of alleviating its symptoms [6]. Therefore, new therapies able to stop the progression of the disease are needed. For these reasons, interest around natural compounds with neuroprotective properties such as caffeine has grown. Caffeine (1,3,7-trimethylxanthin) is a natural alkaloid extracted from coffee, tea Int. J. Mol. Sci. 2020, 21, 4766; doi:10.3390/ijms21134766 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 24 For these reasons, interest around natural compounds with neuroprotective properties such as caffeine has grown. Caffeine (1,3,7-trimethylxanthin) is a natural alkaloid extracted from coffee, tea Int.and J. Mol.cocoa Sci. 2020plants., 21, 4766This psychostimulant has several synonyms, such as theine, mateine2 ofand 22 guaranine, although chemically it is the same molecule [7]. Caffeine is a compound capable of inhibiting lipid peroxidation as well as the formation of reactive oxygen species (ROS) [8]. Therefore, and cocoa plants. This psychostimulant has several synonyms, such as theine, mateine and guaranine, the constant consumption of caffeine acts on neurotoxicity by improving mitochondrial function and although chemically it is the same molecule [7]. Caffeine is a compound capable of inhibiting lipid oxidative stress [9]. Although not fully clarified, the increase in oxidative stress in PD patients is peroxidation as well as the formation of reactive oxygen species (ROS) [8]. Therefore, the constant supported by several factors that occur in the dopaminergic neurons. In particular, α-Syn aggregates consumption of caffeine acts on neurotoxicity by improving mitochondrial function and oxidative could promote the formation of ROS, such as hydrogen peroxide (H2O2), superoxide anion and nitric stress [9]. Although not fully clarified, the increase in oxidative stress in PD patients is supported by oxide, and the consequent lipid peroxidation, DNA damage, increase in the reactive iron level and several factors that occur in the dopaminergic neurons. In particular, α-Syn aggregates could promote reduction in antioxidant species such as glutathione (GSH) and ascorbic acid. In this way, oxidative the formation of ROS, such as hydrogen peroxide (H2O2), superoxide anion and nitric oxide, and stress induces the apoptosis of neurons [10,11]. Moreover, mitochondrial dysfunction also plays an the consequent lipid peroxidation, DNA damage, increase in the reactive iron level and reduction in important role in the pathogenesis of PD [12]. Therefore, alterations in the mitochondrial Complex-I antioxidant species such as glutathione (GSH) and ascorbic acid. In this way, oxidative stress induces of the respiratory chain lead to a reduction in ATP synthesis and increase in ROS, thus favoring the apoptosis of neurons [10,11]. Moreover, mitochondrial dysfunction also plays an important role in neurodegeneration [13]. the pathogenesis of PD [12]. Therefore, alterations in the mitochondrial Complex-I of the respiratory In this regard, the neuroprotective action of caffeine has attracted considerable attention in the chain lead to a reduction in ATP synthesis and increase in ROS, thus favoring neurodegeneration [13]. field of neurodegenerative diseases. Several studies have shown a relationship between regular In this regard, the neuroprotective action of caffeine has attracted considerable attention in the caffeine consumption and a reduced risk of developing PD [14–18]. field of neurodegenerative diseases. Several studies have shown a relationship between regular caffeine The aim of this manuscript was to provide an overview of experimental and clinical studies that consumption and a reduced risk of developing PD [14–18]. report the neuroprotective role of caffeine in the PD. In order to write this review, a search was The aim of this manuscript was to provide an overview of experimental and clinical studies carried out in Pubmed using the following keywords: “caffeine’”, “Parkinson’s Disease”, that report the neuroprotective role of caffeine in the PD. In order to write this review, a search was “experimental models”, “mice” and “rats”. We considered articles published between 2001 and 2020 carried out in Pubmed using the following keywords: “caffeine”, “Parkinson’s Disease”, “experimental demonstrating a neuroprotective role of caffeine in PD. We also provide a summary of current models”, “mice” and “rats”. We considered articles published between 2001 and 2020 demonstrating a clinical trials recorded on ClinicalTrial.gov (https://clinicaltrials.gov/) using the following keywords: neuroprotective role of caffeine in PD. We also provide a summary of current clinical trials recorded on “caffeine’’, “Parkinson’s Disease”. ClinicalTrial.gov (https://clinicaltrials.gov/) using the following keywords: “caffeine”, “Parkinson’s Disease”. 2. Caffeine 2. CaCaffeineffeine belongs to the methylxanthines family, a group of phytocompounds derived from xanthinCaffe.eine Caffeine belongs is mainly to the methylxanthinesextracted from the family, seeds a groupand leaves of phytocompounds of coffee (Coffea derived arabica), from tea xanthine.(Camellia Casinensisffeine) isand mainly cocoa extracted (Theobroma from thecacao seeds L.) and[19] leaves. Caffeine of co ff(1,3,7ee (Co-trimethylxanthin)ffea arabica), tea (Camellia has a sinensisheterocyclic) and structure cocoa (Theobroma formed by cacao pyrimidinedio L.)[19]. Caneffeine and (1,3,7-trimethylxanthin) imidazole rings with imino has a heterocyclicnitrogen at structureposition 9 formed, which byconfers pyrimidinedione the property andof weak imidazole acid. Additionally rings with imino, it contains nitrogen three at positionmethyl groups 9, which in conferspositions the 1, property3 and 7 of[20] weak. Paraxanthin acid. Additionally, (1,7-dimethylxant it containshin) three is the methyl main groups metabolite in positions of caffeine 1, 3 and 7also [20 ].represents Paraxanthin (1,7-dimethylxanthin)an isomer of theobromine is the main metabolite(3,7-dimethylxanthin) of caffeine and and also representstheophylline an isomer(1,3-dimethylxanthin). of theobromine (3,7-dimethylxanthin)Unlike caffeine, paraxanthin and theophylline lacks a (1,3-dimethylxanthin). methyl group at position Unlike ca3ff eine,and paraxanthintheobromine lacks lacks a the methyl