The effect of deep brain stimulation on cortico-subcortical networks in Parkinson's disease patients with freezing of gait: Exhaustive exploration of a basic model.

Current treatments of Parkinson's disease (PD) have limited efficacy in alleviating freezing of gait (FoG). In this context, concomitant deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) has been suggested as a potential therapeutic approach. However, the mechanisms underlying this approach are unknown. While the current rationale relies on network-based hypotheses of intensified disinhibition of brainstem locomotor areas to facilitate the release of gait motor programs, it is still unclear how simultaneous high-frequency DBS in two interconnected basal ganglia nuclei affects large-scale cortico-subcortical network activity. Here, we use a basic model of neural excitation, the susceptible-excited-refractory (SER) model, to compare effects of different stimulation modes of the network underlying FoG based on the mouse brain connectivity atlas. We develop a network-based computational framework to compare subcortical DBS targets through exhaustive analysis of the brain attractor dynamics in the healthy, PD, and DBS states. We show that combined STN+SNr DBS outperforms STN DBS in terms of the normalization of spike propagation flow in the FoG network. The framework aims to move toward a mechanistic understanding of the network effects of DBS and may be applicable to further perturbation-based therapies of brain disorders.

Parkinson's disease patients with freezing of gait (FoG) may be treated by deep brain stimulation, which produces effects mediated by brain networks. Currently, the approach of combined DBS of the subthalamic nucleus and the substantia nigra pars reticulata is investigated for being particularly beneficial for patients with axial symptoms, but the exact mechanisms of this effect are unknown. Here, we present a network-based computational framework using a basic excitable model that enables us to simulate the complete activity patterns of the brain network involved in FoG. These simulations reveal network mechanisms underlying STN+SNr DBS and its efficacy in alleviating FoG. The proposed framework can capture the influence of the DBS target sites on cortico-subcortical networks and help to identify suitable stimulation targets.

A multi-network model of Parkinson's disease tremor: exploring the finger-dimmer-switch theory and role of dopamine in thalamic self-inhibition.

Background. Tremor is a cardinal symptom of Parkinson's disease (PD) that manifests itself through complex oscillatory activity across multiple neuronal populations. According to the finger-dimmer-switch (FDS) theory, tremor is triggered by transient pathological activity in the basal ganglia-thalamo-cortical (BTC) network (the finger) and transitions into an oscillatory form within the inner circuitry of the thalamus (the switch). The cerebello-thalamo-cortical (CTC) network (the dimmer) is then involved in sustaining and amplifying tremor amplitude. In this study, we aimed to investigate the generation and progression dynamics of PD tremor oscillations by developing a comprehensive and interacting FDS model that transitions sequentially from healthy to PD to tremor and then to tremor-off state.Methods.We constructed a computational model consisting of 700 neurons in 11 regions of BTC, CTC, and thalamic networks. Transition from healthy to PD state was simulated through modulating dopaminergic synaptic connections; and further from PD to tremor and tremor-off by modulating projections between the thalamic reticular nucleus (TRN), anterior ventrolateral nucleus (VLa), and posterior ventrolateral nucleus (VLp).Results.Sustained oscillations in the frequency range of PD tremor emerged in thalamic VLp (5 Hz) and cerebellar dentate nucleus (3 Hz). Increasing self-inhibition in the thalamus through dopaminergic modulation significantly decreased tremor amplitude.Conclusion/Significance.Our results confirm the mechanistic power of the FDS theory in describing the PD tremor phenomenon and emphasize the role of dopaminergic modulation on thalamic self-inhibition. These insights pave the way for novel therapeutic strategies aimed at reducing the tremor by strengthening thalamic self-inhibition, particularly in dopamine-resistant patients.

Development strategy of novel drug formulations for the delivery of doxycycline in the treatment of wounds of various etiologies.

Doxycycline hyclate (DOXH) is a broad-spectrum antibiotic derived synthetically from tetracycline. Despite its use in clinical practice for more than 40 years, DOXH remains an effective antibiotic with retained activity. The potential advantages of DOXH for wound healing therapy include its mechanisms of action, such as anti-inflammatory effects, antioxidant properties, modulation of cellular processes, stimulation of collagen synthesis, and antimicrobial activity. As current standards of care aim to improve wound healing by promoting rapid closure, a relevant direction is the development of novel DOXH formulations for parenteral delivery that enhance both skin regeneration and control of infectious conditions. Oral delivery is the most common and commercially available route for administering DOXH therapeutic agents. However, parenteral delivery of DOXH, where the antibiotic substance is not in a solid state (as in powdered or compressed solid form) but rather dissolved in any carrier, presents challenges regarding DOX solubility and the stability of DOXH solutions, which are major factors complicating the development of new formulations for parenteral administration. This review discusses the achievements in research strategies and the development of new pharmaceutical formulations for the delivery of doxycycline in the treatment of wounds of various etiologies.

Development and Validation of a High-Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS/MS) Method for Quantification of Major Molnupiravir Metabolite (ß-D-N4-hydroxycytidine) in Human Plasma.

Molnupiravir is an antiviral drug against viral RNA polymerase activity approved by the FDA for the treatment of COVID-19, which is metabolized to ß-D-N4-hydroxycytidine (NHC) in human blood plasma. A novel method was developed and validated for quantifying NHC in human plasma within the analytical range of 10-10,000 ng/mL using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) to support pharmacokinetics studies. For sample preparation, the method of protein precipitation by acetonitrile was used, with promethazine as an internal standard. Chromatographic separation was carried out on a Shim-pack GWS C18 (150 mm × 4.6 mm, 5 µm) column in a gradient elution mode. A 0.1% formic acid solution in water with 0.08% ammonia solution (eluent A, v/v) and 0.1% formic acid solution in methanol with 0.08% ammonia solution mixed with acetonitrile in a 4:1 ratio (eluent B, v/v) were used as a mobile phase. Electrospray ionization (ESI) was used as an ionization source. The developed method was validated in accordance with the Eurasian Economic Union (EAEU) rules, based on the European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines for the following parameters and used within the analytical part of the clinical study of molnupiravir drugs: selectivity, suitability of standard sample, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification (LLOQ), carryover, and stability.