Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization. This review describes the evolution of the prodrug approach for brain targeting considering the design of prodrugs as active influx substrates or molecules able to inhibit or elude AETs. Moreover, the prodrug approach appears strategic in optimization of the encapsulation of neuroactive drugs in nanoparticulate systems that can be designed to induce their receptor-mediated transport (RMT) across the BBB by appropriate decorations on their surface. Nasal administration is described as a valuable alternative to obtain the brain targeting of drugs, evidencing that the prodrug approach can allow the optimization of micro or nanoparticulate nasal formulations of neuroactive agents in order to obtain this goal. Furthermore, nasal administration is also proposed for prodrugs characterized by peripheral instability but potentially able to induce their targeting inside cells of the brain.

Cognitive Impairment in Inpatients with Prurigo Nodularis and Psychiatric Comorbidities

Background: Prurigo nodularis (PN) is a chronic refractory itchy dermatosis. Although psychiatric comorbidity is known, research in cognitive impairment is lacking. We evaluated the occurrence and types of cognitive impairment in a series of inpatients with PN. Methods: This was a retrospective chart review of all the patients with PN admitted to a referral neurological institute from September 2018 to March 2021. Any neurological and psychiatric disorder, along with neuroactive drugs taken, were concomitantly assessed. Results: A total of 16 patients with PN (median age: 70 years, two males) were selected from a total of 1806 hospital admissions. Most of them had a neurodegenerative cognitive disorder, from mild cognitive impairment (8) to Alzheimer’s disease (1), followed by mixed disorder (degenerative and vascular) in six and vascular dementia in one. Comorbid psychiatric diseases (anxiety and depression) were more common than either individual condition, followed by bipolar disorder, whereas two patients did not show psychiatric manifestations. Most patients were on combined treatment with benzodiazepines and antidepressants. Conclusion: Cognitive impairment can be observed in PN. In addition to screening for psychiatric comorbidity and initiating appropriate treatment or referral, clinicians may also consider the presence of cognitive impairment in PN of both degenerative and vascular origin.

Chemotranscriptome analysis indicates the neurotrophic and neuromodulator effects of a citicoline molecule

Objective: to investigate the effect of citicoline (CTC) on gene transcription.Material and methods. Chemotranscriptome analysis of the CTC molecule was carried out on an NPC.TAK model, provided that the cells were incubated with CTC for 24 hours.Results and discussion. CTC dose-dependently affected the transcription of 8,838 out of 12,716 annotated human genes, mainly by increasing the transcription of the genes involved: 1) in the neurotransmitter metabolism of serotonin (n=36), dopamine (n=32), GABA (n=14), and acetylcholine (n=27); 2) in showing the effects of neurotrophic factors (n=152), including nerve growth factor (n=11); 3) in maintaining the cardiovascular system (vasodilation and cardiac electrical activity; a total of 76 genes). CTC reduced the transcription of the genes, whose protein activity supported inflammation (n=86) and cell division (n=656). CTC elevated the expression of 60 genes involved in triglyceride processing and decreased the expression of 51 genes whose proteins were involved in cholesterol metabolism. CTC increased the transcription of the genes involved in the body’s response to various drugs, including antiepileptic drugs (n=20), dopaminergic agents (n=19), antipsychotics (n=38), anxiolytics (n=21), sedatives (n=22), antidepressants (n=35), anesthetics (n=23), and antidementia drugs (n=11).Conclusion. Chemotranscriptome analysis indicated the positive effect of CTC on neurotransmission, neuroprotection, lipid profile, and a higher neuronal susceptibility to other neuroactive drugs.

Quantification of the influence of drugs on zebrafish larvae swimming kinematics and energetics

The use of zebrafish larvae has aroused wide interest in the medical field for its potential role in the development of new therapies. The larvae grow extremely quickly and the embryos are nearly transparent which allows easy examination of its internal structures using fluorescent imaging techniques. Medical treatment of zebrafish larvae can directly influence its swimming behaviours. These behaviour changes are related to functional changes of central nervous system and transformations of the zebrafish body such as muscle mechanical power and force variation, which cannot be measured directly by pure experiment observation. To quantify the influence of drugs on zebrafish larvae swimming behaviours and energetics, we have developed a novel methodology to exploit intravital changes based on observed zebrafish locomotion. Specifically, by using an in-house MATLAB code to process the recorded live zebrafish swimming video, the kinematic locomotion equation of a 3D zebrafish larvae was obtained, and a customised Computational Fluid Dynamics tool was used to solve the fluid flow around the fish model which was geometrically the same as experimentally tested zebrafish. The developed methodology was firstly verified against experiment, and further applied to quantify the fish internal body force, torque and power consumption associated with a group of normal zebrafish larvae vs. those immersed in acetic acid and two neuroactive drugs. As indicated by our results, zebrafish larvae immersed in 0.01% acetic acid display approximately 30% higher hydrodynamic power and 10% higher cost of transport than control group. In addition, 500 μM diphenylhydantoin significantly decreases the locomotion activity for approximately 50% lower hydrodynamic power, whereas 100 mg/L yohimbine has not caused any significant influences on 5 dpf zebrafish larvae locomotion. The approach has potential to evaluate the influence of drugs on the aquatic animal’s behaviour changes and thus support the development of new analgesic and neuroactive drugs.

Investigating targets for neuropharmacological intervention by molecular dynamics simulations

Medical research has identified over 500 brain disorders. Among these, there are still only very few neuropathologies whose causes are fully understood and, consequently, very few drugs whose mechanism of action is known. No FDA drug has been identified for major neurodegenerative diseases, such as Alzheimer's and Parkinson's. We still lack effective treatments and strategies for modulating progression or even early neurodegenerative disease onset diagnostic tools. A great support toward the highly needed identification of neuroactive drugs comes from computer simulation methods and, in particular, from molecular dynamics (MD). This provides insight into structure–function relationship of a target and predicts structure, dynamics and energetics of ligand/target complexes under biologically relevant conditions like temperature and physiological saline concentration. Here, we present examples of the predictive power of MD for neuroactive ligands/target complexes. This brief survey from our own research shows the usefulness of partnerships between academia and industry, and from joint efforts between experimental and theoretical groups.