パーキンソン病

Optimizing oral levodopa delivery by prolonging duration of effect remains a key challenge in managing OFF periods in Parkinson's disease. IPX203 is an oral modified-release formulation combining immediate-release (IR) and extended-release (ER) levodopa with IR carbidopa, designed to provide rapid onset and sustained exposure. We characterized pharmacokinetics of levodopa and carbidopa following IPX203 compared with IR and controlled-release (CR) levodopa/carbidopa using population pharmacokinetic modeling from a Phase 1 study in healthy volunteers. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling. Formulation-specific absorption models, including a dual-depot model for IPX203, were combined with a shared systemic disposition model. The models adequately described observed levodopa and carbidopa concentrations across formulations. Marked formulation-dependent differences in levodopa exposure were driven by absorption. IR-levodopa/carbidopa produced rapid absorption with peak concentrations followed by a steep decline, consistent with elimination-rate-limited pharmacokinetics. CR-levodopa/carbidopa showed delayed absorption with lower peak concentrations and limited time within the expected therapeutic range (750-1000 ng/mL). In contrast, IPX203 exhibited biphasic absorption, with an initial IR-driven peak and sustained concentrations from the ER component, consistent with rate-limited absorption and prolonged intestinal residence. This resulted in reduced peak-trough fluctuation and longer duration within therapeutic range. Carbidopa profiles were qualitatively similar, with higher absolute exposure for IPX203. Model-based simulations of commonly used dosing regimens suggested that IPX203 administered every 6 h achieved the most stable levodopa concentrations. These findings indicate that IPX203 provides a distinct exposure profile characterized by rapid onset and sustained levodopa exposure driven by controlled absorption.

OBJECTIVE: To investigate whether hyperoside (HYP), the main active ingredients of Wuzi Yanzong Pill, can reduce oxidative stress (OS) damage and treat Parkinson's disease (PD) by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. METHODS: MPTP-induced PD mouse model was established and animals were divided into 5 groups by random number table method: control group, MPTP group (15, 20, and 30 mg/kg on days 1, 2 and 3-7, respectively), and MPTP+HYP low-, medium-, and high-dose groups (25, 50, and 100 mg·kg-1·d-1, respectively). Behavioral tests were conducted and protein expression levels of tyrosine hydroxylase (TH), Nrf2, HO-1, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) were analyzed using Western blot. Glutathione (GSH), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels were measured by ELISA. Molecular docking and dynamics simulations were performed on HYP and Nrf2, and neuronal apoptosis was detected by TUNEL assay. Multivariate statistical analysis was used to investigate the correlation between HYP's therapeutic effect on PD and OS via the Nrf2/HO-1 pathway. In the SH-SY5Y cell model (MPP+ and ML385), cell viability and toxicity were assessed with cell counting kit-8 and lactate dehydrogenase assays, and protein expression levels and OS indicatars were also measured. RESULTS: In animal experiments, HYP intervention improved motor abilities, increased TH, Nrf2, HO-1, and Bcl-2 expressions, and reduced Bax expression compared to the MPTP group (P<0.05 or P<0.01). It also elevated GSH, GSH-Px, SOD, and CAT levels, decreased MDA, and reduced neuronal apoptosis (P<0.05 or P<0.01). Molecular docking and dynamics showed HYP binds effectively to Nrf2. Multivariate analysis revealed a strong correlation between HYP's therapeutic effect on PD and OS via the Nrf2/HO-1 pathway. In cell experiments, ML385 inhibited Nrf2/HO-1 activation by HYP (P<0.05 or P<0.01), diminishing its effect on OS and apoptosis. CONCLUSION: HYP can reduce OS and apoptosis by activating the Nrf2/HO-1 pathway, thereby exerting a therapeutic effect in PD.

Neurodegeneration results from the convergence of several molecular processes, including inflammation in the brain (i.e., neuroinflammation), elevated levels of free radicals that damage cells, mitochondrial dysfunction, and the inability to remove damaged proteins from the brain. Even though many agents provide neuroprotection in research models, their clinical use is limited because they cannot effectively cross the blood-brain barrier to reach the areas of the brain where they are needed. Limitations include the inability to cross the blood-brain barrier, poor bioavailability, rapid metabolism and clearance, non-specific targeting, efflux by transport proteins, toxicity, and low solubility and stability. The classification of micronutrients (e.g., vitamins, polyphenols, minerals), which are naturally present antioxidants and anti-inflammatory substances, plays a role in modulating the most important signaling pathways in the body, including those mediating the inflammatory response (i.e., NF-κB and NLRP3) and the process that causes glial cell death (i.e., JAK/STAT). Micronutrients have a significant drawback for therapeutic use because they are rapidly metabolized and cannot cross the blood-brain barrier. Developments in synthetic biomaterials and nanotechnology offer a potential avenue for addressing the challenges of delivering micronutrients to the brain by targeting them to specific areas and releasing them over a sustained period. This study presents current information on the mechanisms by which micronutrients modulate molecular pathways and their potential application in emerging biomaterials to develop a new class of neuroprotective therapeutic agents that may ultimately be used to treat patients with degenerative diseases (e.g., Alzheimer's, Parkinson's, and Huntington's). Additionally, clinical challenges are addressed to translate these products from the laboratory to the clinic. The idea presented in this review connects molecular neuromodulation via micronutrients and bioactive nutraceuticals with a new strategy for pharmacological delivery using biomaterials. Instead of considering nutrition and those biomaterials as separate therapeutic areas, an integrated mechanistic model is presented that shows how micronutrients can act as endogenous pathway regulators and how biomaterials can enhance pharmacokinetics and targeting.

Phosphorus magnetic resonance spectroscopy (31P-MRS) enables noninvasive measurement of brain metabolism, yet its reproducibility in clinical settings remains unclear. We systematically assessed intrasession and intersession variability as well as interindividual differences of key phosphorus metabolites at 3 T in healthy individuals and persons with Parkinson's disease under various experimental conditions. Intersession variability, as measured by coefficients of variation (CoVs) increased notably for longer scan intervals (~1 year), and metabolite ratios from well-resolved spectral signals (i.e., adenosine triphosphate [ATP], phosphocreatine [PCr], and intracellular inorganic phosphate [Pi]) exhibited consistently higher stability compared with ratios calculated from metabolite signals overlapping on the spectrum (e.g., total nicotinamide adenine dinucleotide [tNAD], as well as phosphate monoesters [PMEs] and phosphate diesters [PDEs]). Test-retest variability ranged from ~5 to 25 CoV%, where PCr, ATP-α, and ATP-γ were the most stable while glycerophosphocholine (GPC), glycerophosphoethanolamine (GPE), phosphoethanolamine (PE), and tNAD varied considerably. Interindividual variability was found to be higher than intraindividual variability for all metabolite ratios, ranging from ~9 to 33 CoV%. By systematically quantifying intraindividual and interindividual variability, as well as providing explicit sample size recommendations, this study facilitates more reliable longitudinal and cross-sectional clinical trials and translational studies of brain metabolism featuring 31P-MRS.

N-methyl-D-aspartate (NMDA) receptor encephalitis stands as the most common form of autoimmune encephalitis in young adults, characterized by a spectrum of distressing symptoms such as seizures, behavioral disruptions, autonomic dysfunction, and memory impairment. We present a noteworthy case involving a young adult male exhibiting seizures and renal failure, initially prompting an evaluation for vasculitis, hyperuricemia-induced acute kidney injury (AKI), and rhabdomyolysis-induced AKI. However, subsequent findings revealed the presence of NMDA receptor antibodies, and a renal biopsy confirmed tubulointerstitial nephritis. This case sheds light on the association between renal failure and NMDA receptor antibody-associated encephalitis, marking a rare instance in our knowledge.