Motor Function Efficacy of Pharmacological Treatments Targeting Energy Metabolism, in Parkinson's Patients

Motor Function Efficacy of Pharmacological Treatments Targeting Energy Metabolism, in Parkinson's Patients

-Clinical Efficacy of Pharmacological Treatments Targeting Energy Metabolism, Evaluated by Gait Analysis, on Motor Function in Parkinson's Disease Patients

Consistent evidence suggests that mitochondrial dysfunction plays a crucial role in Parkinson¿s disease pathogenesis. Inhibition of complex I of the mitochondrial electron transport chain is sufficient to reproduce biochemical and pathological features of Parkinson¿s Disease in animal models (PD). Alterations of mitochondrial energy metabolism may intervene in PD pathogenesis by inducing inflammation, generation of reactive oxygen species (ROS), and neurodegeneration. The Nuclear factor erythroid 2-related factor 2 (Nrf2) is a regulator both of mitochondrial function and biogenesis, and of cellular resistance to oxidative stress, and may represent a novel target of PD disease-modifying therapies. The aims of the present study are to validate indicators of energy metabolism as biomarkers in PD patients and to evaluate the efficacy of drugs and natural food supplements acting on the Nrf2 pathway in improving motor impairment and Gait in PD patients.

Bradykinesia, causing impairment of gait and an associated significant risk of falls, is among the most debilitating core features of Parkinson¿s disease (PD), a movement disorder characterized by the degeneration of Substantia nigra dopaminergic neurons. The pacemaking action potential firing activity of nigral neurons requires high energy consumption and is coupled to large cytosolic calcium oscillations, which influence mitochondrial respiration, energy metabolism, and reactive oxygen species (ROS) production. Mitochondrial dysfunction, on the other hand, can drive dysregulation of calcium homeostasis, especially in dopaminergic neurons, and is recognized as a key component in PD progression. Notably, both calcium-binding and increased ROS production, resulting from inefficiencies in the mitochondrial electron transport chain, can trigger alpha-synuclein aggregation, thus contributing to neuronal loss and disease progression in PD. The Nuclear factor erythroid 2- related factor 2 (Nrf2) is a regulator of mitochondrial function and biogenesis, and cellular resistance to oxidative stress. Bioactive compounds activating the Nrf2 signaling pathway ameliorate Parkinsonian phenotypes in experimental models, suggesting the Nrf2 pathway potential novel therapeutic target in PD. Bradykinesia, causing impairment of gait and an associated significant risk of falls, is among the most debilitating core features of PD. PD gait is characterized by shuffling steps accompanied by a stooped posture. In advanced PD, other complications may arise such as disturbances in speech, gait, posture, and balance, as well as hypomimia, impaired decision-making, alertness, and regulation of emotions. The increased energy demand associated with bradykinesia is coupled with the impairment of energy metabolism in Parkinsonians, negatively affecting walking, gait, and postural stability, suggesting that the modulation of mitochondrial energy metabolism may ameliorate gait and postural stability in Parkinsonians. Cardinal symptoms of PD: Tremors, Rigidity, Bradykinesia, and postural instability, all elements that lead in almost all patients to a walking disorder. In fact, walking in Parkinson's disease is present since in the early stages of the disease, the step is reduced in length and speed, the swinging phase of the step (swing) is reduced, while the support (Stance) single and double is increased in duration. Progression as well as the severity of disease over time, leads to a significant increase in the risk of falls, inducing a reduction in autonomy in daily living activity. As mentioned Gait is influenced in a principal way. Bipedal walking, in humans, is well orchestrated, consistent with the intrinsic "kinetic melody". This "melody" in subjects with PD is altered appears clear that the analysis of the gait represents a key element for establishing functional recovery therapies aimed at restoring motor skills. Therefore, it seems sensible to hypothesize that energy metabolism parameters may represent reliable biomarkers in PD and that the Nrf2 pathway may be a new therapeutic target for the recovery of motor function in PD patients. Not only that, but the identification of reliable biomarkers that are easy to measure over time can aid in the diagnosis, and possible prognosis, and improve management. In support of this view, PD pathogenesis is known to involve the loss of the homeostatic functions controlling mitochondrial energy metabolism. The transcription factor Nrf2 is a master controller of these functions. Notably, Nrf2 activity is compromised during aging and in neurodegenerative diseases. The investigators hypothesize that energy metabolism parameters may represent reliable biomarkers in PD and that the Nrf2 pathway may be a novel therapeutic target for the rescue of motor function in Parkinsonians. The identification of reliable biomarkers, easy to measure over time, is fundamental to facilitating diagnosis, prognosis, and better management of PD patients. The proposed study on PD patients will provide information immediately transferable to the clinical practice. Additionally, the clinical trial planned in the present project will provide substantial information regarding the effectiveness of different pharmacological approaches targeting the Nrf2 pathway in ameliorating gait and balance in Parkinsonians, thus reducing the substantial social and economic burden of PD to society, patients, and caregivers. Many drugs and natural food supplements acting on the Nrf2 pathway are available; therefore, the transfer to the clinical practice of the results of the present project is expected to be rapid.

25 M-PD (H&Y< 2.5) and 25 S-PD (H&Y > 2.5) patients with idiopathic PD will be enrolled sequentially in the randomized double-blind, double-dummy study.

MD UPDRs : Four Parts: II questionary by Parkinsonian or care-given, III-IV: Motor Part and Complication by neurologist , Each item rate from 0: no sign to 4: max sign PDQ39 questionary performed by Parkinsonian each item rate from 0: never, to 5:always. Gait Analysis following spatio-temporal parameters will be taken in to account: Right and Left Step Length, Stride time% Stance Swing , Double support t, Mean Velocity, Cadence, Stepwidth, and t for turning task:• Number of steps to complete the lap,• Lap time, Metabolomic Variables: Steady State oxygen uptake (VO2, mlkg-1min-1) and carbon dioxide production (VCO2), heart rate (HR), Walking energy cost per unit of time-WECt8Jkg-1min-1),Metabolic human blood variabes : G6PD mU/109 erytrocytes, CAT, GPx, NQO1,HO-1,SOD: U/mg protein, GSH mmol GSH/l, MDA mmol/MDA/l,NrF2 gene expression

Animal models allow an in-depth analysis, in strictly controlled experimental conditions, of several biological parameters, both at the peripheral level and in the brain, in relation to the expression of a motor phenotype. First, protein levels and mRNA expression of markers of energy metabolism will be measured both in the blood and in relevant brain areas of a group of PD and control rodents.. Electrophysiological recordings and intracellular calcium measurements from striatum and substantia nigra neurons in acute slices of PD and control rodents will allow an analysis of the correlation between the biomarker profile, the neuronal function, and the parkinsonian motor behavior. In a second phase, we will test the efficacy of in vivo treatments with different modulators of the Nrf2 pathway in rescuing the PD model¿s motor behavior, energy metabolism biomarkers, and both striatal and substantia nigra neuron physiology. See metabolic human blood variables

Inclusion Criteria: Patient with rigid-acinetic bilateral PD form At least 5 years of disease history H&Y between 2-3.5 Stable drug therapy response without any change performed in the 3 months before the study. MMSE>24/30 (Mini-Mental State Examination) No severe gastrointestinal pathologies. Exclusion Criteria: Systemic illness Presence of cardiac pacemaker Presence of deep brain stimulation Presence of severe dysautonomia with marked hypotension Obsessive-Compulsive Disorder (OCD) Major depression Dementia History or active neoplasia Pregnancy Lack of autonomy in walking; Malabsorption and gastrointestinal disorders; Gluten intolerance Ipotiroidism

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