Transport of drugs across the blood-brain barrier by nanoparticles.

Piracetam and other structurally related nootropics

Neuroinflammation plays a key role in the pathogenesis of Parkinson's disease (PD). Epidemiologic, animal, human, and therapeutic studies support the role of oxidative stress and inflammatory cascade in initiation and progression of PD. In Parkinson's disease pathophysiology, activated glia affects neuronal injury and death through production of neurotoxic factors like glutamate, S100B, tumor necrosis factor alpha (TNF-α), prostaglandins, and reactive oxygen and nitrogen species. As disease progresses, inflammatory secretions engage neighboring cells, including astrocytes and endothelial cells, resulting in a vicious cycle of autocrine and paracrine amplification of inflammation leading to neurodegeneration. The exact mechanism of these inflammatory mediators in the disease progression is still poorly understood. In this review, we highlight and discuss the mechanisms of oxidative stress and inflammatory mediators by which they contribute to the disease progression. Particularly, we focus on the altered role of astroglial cells that presumably initiate and execute dopaminergic neurodegeneration in PD. In conclusion, we focus on the molecular mechanism of neurodegeneration, which contributes to the basic understanding of the role of neuroinflammation in PD pathophysiology.

The Role of Inflammatory and Oxidative Stress Mechanisms in the Pathogenesis of Parkinson’s Disease: Focus on Astrocytes

There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities. Subgroup 2 drugs include levetiracetam, seletracetam and brivaracetam, which demonstrate antiepileptic activity, although their cognitive effects are unclear. Subgroup 3 includes piracetam derivatives with unknown clinical efficacies, and of these nefiracetam failed to improve cognition in post-stroke patients and rolipram is currently in clinical trials as an antidepressant. The remaining compounds of this subgroup are at various preclinical stages of research. The modes of action of piracetam and most of its derivatives remain an enigma. Differential effects on subtypes of glutamate receptors, but not the GABAergic actions, have been implicated. Piracetam seems to activate calcium influx into neuronal cells; however, this function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells. Although subgroup 2 compounds act via binding to another neuronal receptor (synaptic vesicle 2A), some of the subgroup 3 compounds, such as nefiracetam, are similar to those of subgroup 1. Based on calculations of the efficacy rates, our assessments indicate notable improvements in clinical outcomes with some of these agents.

Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders.

The field of nanotechnology, which aims to control and utilize matter generally in 1-100 nm range, has been at the forefront of pharmaceutical development. Nanoparticulate delivery systems, with their potential to control drug release profiles, prolonging the presence of drugs in circulation, and to target drugs to a specific site, hold tremendous promise as delivery strategies for therapeutics. Growth factors are endogenous polypeptides that initiate intracellular signals to regulate cellular activities, such as proliferation, migration and differentiation. With improved understanding of their roles in physiopathology and expansion of their availability through recombinant technologies, growth factors are becoming leading therapeutic candidates for tissue engineering approaches. However, the outcome of growth factor therapeutics largely depends on the mode of their delivery due to their rapid degradation in vivo, and non-specific distribution after systemic administration. In order to overcome these impediments, nanoparticulate delivery systems are being harnessed for spatiotemporal controlled delivery of growth factors. This review presents recent advances and some disadvantages of various nanoparticulate systems designed for effective intact growth factor delivery. The therapeutic applications of growth factors delivered by such systems are reviewed, especially for bone, skin and nerve regeneration as well as angiogenesis. Finally, future challenges and directions in the field are presented in addition to the current limitations.

Nanoparticulate Systems for Growth Factor Delivery

The study examined the antiparkinsonian effect of nerve growth factor adsorbed on the surface of polybutylcyanoacrylate nanoparticles coated with polysorbate-80 surfactant. The parkinsonian syndrome in C57B1/6 mice was provoked by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The basic symptoms of the parkinsonian syndrome decreased under the action of the nerve growth factor adsorbed on nanoparticles coated with polysorbate-80, which was seen from decreased rigidity and increased locomotor activity compared to control mice receiving with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine alone. This effect of nerve growth factor on nanoparticles persisted after 7 and 21 days after single injection of the neurotoxin. These data attest to the possibility of using nanoparticles prepared from amphiphilic polymers and coated with polysorbate-80 for the delivery of nerve growth factor into the brain during systemic treatment.

Antiparkinsonian effect of nerve growth factor adsorbed on polybutylcyanoacrylate nanoparticles coated with polysorbate-80.

ЖУРНАЛ НЕВРОЛОГИИ И ПСИХИАТРИИ, 7, 2015 Процесс образования свободных радикалов относится к универсальным механизмам жизнедеятельности любой живой клетки. Их основным источником является процесс трансформации кислорода в митохондриях. Поступающий в клетку кислород подвергается полному восстановлению до воды. Однако в процессе аэробного метаболизма при неполном восстановлении кислорода в качестве промежуточных продуктов образуются свободные радикалы (СР). Они представляют собой различные по атомному составу химические вещества, общей особенностью которых является наличие неспаренного электрона на одной из их орбит. В результате этого СР являются нестабильными веществами, обладающими высокой химической активностью. Свободные радикалы при контролируемом образовании играют важную физиологическую роль: регуляция сосудистого тонуса, проведение возбуждения, участие в реакциях воспаления, механизмах репарации, элиминации отживших клеток [6, 12, 43]. В то же время избыточное образование СР ассоциируется с патологическими процессами. Интенсификация свободнорадикальных процессов в организме может быть вызвана как усилением образования активных форм кислорода (АФК), свободных радикалов и низкомолекулярных эндогенных проокcидантов, так и снижением эффективности действия биологических систем утилизации и детоксикации АФК и СР. Образование СР могут провоцировать различные процессы, сопровождающие жизнедеятельность организма: стрессы, ионизирующее излучение, токсины и т.д. СР участвуют в патогенезе большого количества заболеваний — ишемии, сахарного диабета, черепно-мозговой травмы, онкологии, атеросклероза, катаракты, преждевременного старения, болезни Паркинсона (БА), болезни Альцгеймера, хореи Гентингтона [14, 26, 44].

[Oxidative stress and Parkinson's disease: mechanisms and perspectives of treatment].

New dibenzofuranone-oxime derivatives were designed based on active structures of oxime esters. Compounds of the proposed group were synthesized using 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and aromatic acid chlorides. The anticonvulsant activity of the new compounds was studied. The structure— activity relationship was analyzed. Compound 1a [3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one O-(3,4-dichlorobenzoyl)oxime] was the most active compound after i.p. injection to mice in the maximal electroshock test over a wide dose range of 20 – 100 mg/kg. Compound 1a at doses of 10 and 30 mg/kg exhibited antihypoxic activity in a hypoxia test with hypercapnia in a hermetic chamber and anti-ischemic activity at a dose of 10 mg/kg in a rat ischemic stroke model.

Synthesis of Dibenzofuranone-Oxime Derivatives with Anticonvulsant, Antihypoxic, and Anti-Ischemic Activity

Novel thiocoumarins and quinolin-2-ones were synthesized and screened for anticonvulsant activity. The structure–activity relationship of a series of synthesized compounds and previously prepared coumarin derivatives was analyzed. The methyl ester of N-(3-nitro-2-oxo-1,2-dihydroquinolin-4-yl)-4-aminobutyric acid (3a) at a dose of 12.5 mg/kg (i.p.) had the greatest anticonvulsant activity in mouse tests.

Synthesis and Anticonvulsant Activity of 4-Amino-3-Nitro-1-Thiocoumarins and 4-Amino-3-Nitroquinolin-2-Ones

The synthesis and anticonvulsant activity of new coumarin derivatives are reported. N-(3-Nitrocoumarin-4-yl)-4-aminobutyric acid (1a) at doses of 60 and 80 mg/kg (in the MES test) and methyl N-(3,6-dinitrocoumarin-4-yl)-4-aminobutyrate (1e) at doses of 20 and 40 mg/kg (in the corazole antagonism test) possessed the greatest anticonvulsant activity of the synthesized compounds. The results indicated that the coumarin derivatives were promising for further development as potential anticonvulsant agents.

L. N. Nerobkova

Papers

Antiparkinsonian effect of nerve growth factor adsorbed on polybutylcyanoacrylate nanoparticles coated with polysorbate-80.

[Oxidative stress and Parkinson's disease: mechanisms and perspectives of treatment].

Synthesis of Dibenzofuranone-Oxime Derivatives with Anticonvulsant, Antihypoxic, and Anti-Ischemic Activity

Synthesis and Anticonvulsant Activity of 4-Amino-3-Nitro-1-Thiocoumarins and 4-Amino-3-Nitroquinolin-2-Ones

Synthesis and Anticonvulsant Activity of N-Substituted 4-Amino-3-Nitrocoumarins