Solid lipid nanoparticles loaded with lipoyl-memantine codrug: preparation and characterization.

Solid lipid nanoparticles (SLNs) are considered very attractive drug-delivery systems (DDS) able to enhance the efficacy of some therapeutic agents in several pathologies difficult to treat in a conventional way. Starting from these evidences, this study describes the preparation, physicochemical characterization, release, and in vitro cytotoxicity of stealth SLNs as innovative approach to improve solubility and absorption through the gastrointestinal tract of lipoyl-memantine (LA-MEM), a potential anti-Alzheimer codrug. Physico-chemical properties of LA-MEM loaded SLNs have been intensively investigated.

Lipid nanocarriers containing a levodopa prodrug with potential antiparkinsonian activity.

This paper describes the production, characterization and in vivo activity of lipid nanocarriers (LN) containing a levodopa prodrug (LD-PD) with therapeutic potential in Parkinson's disease. LD is the mainstay of the pharmacotherapy of Parkinson's disease. However, after a good initial response, motor fluctuations, dyskinesia and loss of efficacy, develop over time, partly due to oscillations in plasma and brain levels of the drug.

Haloperidol metabolite II prodrug: asymmetric synthesis and biological evaluation on rat C6 glioma cells.

In a previous work we reported the antiproliferative effects of (±)-MRJF4, a novel haloperidol metabolite II (HP-mII) (a sigma-1 antagonist and sigma-2 agonist) prodrug, obtained through conjugation to 4-phenylbutyric acid (PhBA) [a histone deacetylase inhibitor (HDACi)] via an ester bond. As a continuation of this work, here we report the asymmetric synthesis of compounds (R)-(+)-MRJF4 and (S)-(-)-MRJF4 and the evaluation of their biological activity on rat C6 glioma cells, derived from glioblastoma multiforme (GBM), which is the most common and deadliest central nervous system (CNS) invasive malignancy. Favourable physicochemical properties, high permeability in the parallel artificial membrane permeability assay (PAMPA), good enzymatic and chemical stability, in vivo anticancer activity, associated with the capacity to reduce cell viability and to increase cell death by apoptosis, render compound (R)-(+)-MRJF4 a promising candidate for the development of a useful therapeutic for gliomas therapy.

Synthesis of a novel cyclic prodrug of S-allyl-glutathione able to attenuate LPS-induced ROS production through the inhibition of MAPK pathways in U937 cells.

A novel cyclic prodrug of S-allyl-glutathione (CP11), obtained by using an acyloxy-alkoxy linker, was estimated for its pharmacokinetic and biological properties. The stability of CP11 was evaluated at pH 1.2, 7.

Protective effects of cyclosativene on H2O 2-induced injury in cultured rat primary cerebral cortex cells.

Sesquiterpenes have attracted much interest with respect to their protective effect against oxidative damage that may be the cause of many diseases including several neurodegenerative disorders and cancer. Our previous unpublished work suggested that cyclosativene (CSV), a tetracyclic sesquiterpene, has antioxidant and anticarcinogenic features. However, little is known about the effects of CSV on oxidative stress induced neurotoxicity.

Evaluation of cytotoxic, oxidative stress and genotoxic responses of hydroxyapatite nanoparticles on human blood cells.

The present study was designed to investigate genotoxic and cytotoxic effects and oxidative damage of increasing concentrations of nano-hydroxyapatite (5, 10, 20, 50, 75, 100, 150, 300, 500 and 1000 ppm) in primary human blood cell cultures. Cell viability was detected by [3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay and lactate dehydrogenase release, while total antioxidant capacity and total oxidative stress levels were determined to evaluate the oxidative injury. The DNA damage was also analyzed by sister chromatid exchange, micronuclei, chromosome aberration assays and 8-oxo-2-deoxyguanosine level as indicators of genotoxicity.

A glutathione derivative with chelating and in vitro neuroprotective activities: synthesis, physicochemical properties, and biological evaluation.

Metal-ion dysregulation and oxidative stress have been linked to the progressive neurological decline associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Herein we report the synthesis and chelating, antioxidant, and in vitro neuroprotective activities of a novel derivative of glutathione, GS(HQ)H, endowed with an 8-hydroxyquinoline group as a metal-chelating moiety. In vitro results showed that GS(HQ)H may be stable enough to be absorbed unmodified and arrive intact to the blood-brain barrier, that it may be able to remove Cu(II) and Zn(II) from the Aβ peptide without causing any copper or zinc depletion in vivo, and that it protects SHSY-5Y human neuroblastoma cells against H2 O2 - and 6-OHDA-induced damage.

Neuroprotective effects of farnesene against hydrogen peroxide-induced neurotoxicity in vitro.

Oxidative stress is highly damaging to cellular macromolecules and is also considered a main cause of the loss and impairment of neurons in several neurodegenerative disorders. Recent reports indicate that farnesene (FNS), an acyclic sesquiterpene, has antioxidant properties. However, little is known about the effects of FNS on oxidative stress-induced neurotoxicity.

New flurbiprofen derivatives: synthesis, membrane affinity and evaluation of in vitro effect on β-amyloid levels.

Alzheimer's disease (AD) is characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss. Current therapeutic strategies for the treatment of AD have been directed to a variety of targets with the aim of reversing or preventing the disease but, unfortunately, the available treatments often produce no significant clinical benefits. During the last decades compounds that inhibit or modulate γ-secretase, reducing β amyloid (Aβ) levels, have been considered as potential therapeutics for AD.

Memantine-sulfur containing antioxidant conjugates as potential prodrugs to improve the treatment of Alzheimer's disease.

The approved treatments for Alzheimer's disease (AD) exploit mainly a symptomatic approach based on the use of cholinesterase inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Natural antioxidant compounds, able to pass through the blood-brain barrier (BBB), have been extensively studied as useful neuroprotective agents. A novel approach towards excitotoxicity protection and oxidative stress associated with excess β amyloid (Aβ) preservation in AD is represented by selective glutamatergic antagonists that possess as well antioxidant capabilities.

Ibuprofen and lipoic acid conjugate neuroprotective activity is mediated by Ngb/Akt intracellular signaling pathway in Alzheimer's disease rat model.

Background: Alzheimer's disease (AD) is a frequent form of senile dementia. Neuroglobin (Ngb) has a neuroprotective role and decreases Aβ peptide levels. Ngb, promoting Akt phosphorylation, activates cell survival involving cyclic-nucleotide response element-binding protein (CREB).

Modulation of monoaminergic transporters by choline-containing phospholipids in rat brain.

Choline-containing phospholipids were proposed as cognition enhancing agents, but evidence on their activity is controversial. CDP-choline (cytidine-5´-diphosphocholine, CDP) and choline alphoscerate (L-alpha-glycerylphosphorylcholine, GPC) represent the choline-containing phospholipids with larger clinical evidence in the treatment of sequelae of cerebrovascular accidents and of cognitive disorders. These compounds which display mainly a cholinergic profile interfere with phospholipids biosynthesis, brain metabolism and neurotransmitter systems.

(R)-α-lipoyl-glycyl-L-prolyl-L-glutamyl dimethyl ester codrug as a multifunctional agent with potential neuroprotective activities.

The (R)-α-lipoyl-glycyl-L-prolyl-L-glutamyl dimethyl ester codrug (LA-GPE, 1) was synthesized as a new multifunctional drug candidate with antioxidant and neuroprotective properties for the treatment of neurodegenerative diseases. Physicochemical properties, chemical and enzymatic stabilities were evaluated, along with the capacity of LA-GPE to penetrate the blood-brain barrier (BBB) according to an in vitro parallel artificial membrane permeability assay for the BBB. We also investigated the potential effectiveness of LA-GPE against the cytotoxicity induced by 6-hydroxydopamine (6-OHDA) and H2O2 on the human neuroblastoma cell line SH-SY5Y by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay.

Transdermal donepezil on the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of senile dementia, characterized by cognitive deficits related to degeneration of cholinergic neurons. The first anti-Alzheimer drugs approved by the Food and Drug Administration were the cholinesterase inhibitors (ChEIs), which are capable of improving cholinergic neurotransmission by inhibiting acetylcholinesterase. The most common ChEIs used to treat cognitive symptoms in mild to moderate AD are rivastigmine, galantamine, and donepezil.

Designing prodrugs for the treatment of Parkinson's disease.

Introduction: Current Parkinson's disease (PD) therapy is essentially symptomatic, and l-Dopa (LD), is the treatment of choice in more advanced stages of the disease. However, motor complications often develop after long-term treatment, and at this point physicians usually prescribe adjuvant therapy with other classes of antiparkinsonian drugs, including dopamine (DA) agonists, catechol-O-methyl transferase (COMT) or monoamine oxidase (MAO)-B inhibitors. In order to improve bioavailability, the prodrug approach appeared to be the most promising, and some antiparkinsonian prodrugs have been prepared in an effort to solve these problems.

L-Dopa prodrugs: an overview of trends for improving Parkinson's disease treatment.

L-Dopa is the mainstay of Parkinson's disease therapy; this drug is usually administered orally, but it is extensively metabolized in the gastrointestinal tract, so that relatively little arrives in the bloodstream as intact L-Dopa. The peripheral conversion of L-Dopa by amino acid decarboxylase to dopamine is responsible for the typical gastrointestinal and cardiovascular side effects. To minimize the conversion to dopamine outside the central nervous system, L-Dopa is usually given in combination with peripheral inhibitors of amino acid decarboxylase.

Potential antibacterial activity of carvacrol-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles against microbial biofilm.

The ability to form biofilms contributes significantly to the pathogenesis of many microbial infections, including a variety of ocular diseases often associated with the biofilm formation on foreign materials. Carvacrol (Car.) is an important component of essential oils and recently has attracted much attention pursuant to its ability to promote microbial biofilm disruption.

Drug delivery strategies for Alzheimer's disease treatment.

Introduction: Current Alzheimer's disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence.

Areas Covered: In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools.

Ibuprofen and glutathione conjugate as a potential therapeutic agent for treating Alzheimer's disease.

Non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, we synthesized a molecular combination of glutathione (GSH) and ibuprofen (IBU) via an amide bond and investigated its potential for targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation are related to AD. Evaluation of its physicochemical and in-vitro antioxidant properties indicated that compound 1 exhibits good stability toward human plasma enzymatic activity, and, like GSH, displays in-vitro free radical scavenging activity in a time and concentration-dependent manner.

Effect of choline-containing phospholipids on brain cholinergic transporters in the rat.

The influence of one week treatment with the choline-containing phospholipids cytidine-5'-diphosphocholine (CDP-choline) and choline alphoscerate (L-alpha-glyceryl-phosphorylcholine) at choline-equivalent doses (CDP-choline: 325 mg/kg/day; choline alphoscerate: 150 mg/kg/day) on vesicular acetylcholine transporter (VAChT), on choline transporter (CHT) and on acetylcholine (ACh) concentrations was investigated in rat frontal cortex, striatum and cerebellum. ACh was assayed by HPLC with electrochemical detection, VAChT by Western blot, ELISA and immunohistochemistry, CHT by Western blot and immunohistochemistry. After CDP-treatment, ACh levels were slightly increased in the frontal cortex, not substantially different in the striatum, and reduced significantly in the cerebellum compared to controls.

CNS delivery of L-dopa by a new hybrid glutathione-methionine peptidomimetic prodrug.

Parkinson's disease (PD) is a neurodegenerative disorder associated primarily with loss of dopamine (DA) neurons in the nigrostriatal system. With the aim of increasing the bioavailability of L: -dopa (LD) after oral administration and of overcoming the pro-oxidant effect associated with LD therapy, we designed a peptidomimetic LD prodrug (1) able to release the active agent by enzyme catalyzed hydrolysis. The physicochemical properties, as well as the chemical and enzymatic stabilities of the new compound, were evaluated in order to check both its stability in aqueous medium and its sensitivity towards enzymatic cleavage, providing the parent LD drug, in rat and human plasma.

NOS-mediated morphological and molecular modifications in rats infused with Aβ (1-40), as a model of Alzheimer's disease, in response to a new lipophilic molecular combination codrug-1.

Alzheimer's disease is a neurodegenerative pathology due to the presence of β-amyloid plaques at brain level and hippocampus level and associated with the loss of memory speech and learning. At the basis of these effects lie molecular mechanisms which include nitric oxide metabolic pathway, whose involvement in the occurrence of morphological modifications related to such neurodegenerative process is suggested. Current evidences show that the non-steroidal anti-inflammatory drug ibuprofen posses a protective effect against the development of the disease, substantially delaying its onset; furthermore (R)-α-lipoic acid seems to have an antioxidant ameliorating effect on disease progression.

Novel imidazoline compounds as partial or full agonists of D2-like dopamine receptors inspired by I2-imidazoline binding sites ligand 2-BFI.

Based on the well known biological versatility of the imidazoline nucleus, we prepared the novel derivatives 3a-k inspired by 2-BFI scaffold to assess imidazoline molecules as D(2)-like dopamine receptor ligands. Conservative chemical modifications of the lead structure, such as the introduction of an hydroxy group in the aromatic ring alone or associated with N-benzyl substitution, provided partial (3f) or nearly full (3e and 3h) agonists, all endowed with D(2)-like potency comparable to that of dopamine.

Ibuprofen and lipoic acid diamides as potential codrugs with neuroprotective activity.

Current evidences support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, our attention was focused on ibuprofen (IBU) used in clinical trails to prevent Alzheimer's disease, and (R)-alpha-lipoic acid (LA) considered as a potential neuroprotective agent in AD therapy. In particular, we investigated a series of lipophilic molecular combinations obtained by joining (R)-alpha-lipoic acid and ibuprofen via an amide bond.

Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs.

L-DOPA, the immediate biological precursor of dopamine, is still considered the drug of choice in the treatment of Parkinson's disease. However, therapy with L-DOPA is associated with a number of acute problems. With the aim to increase the bioavailability after oral administration, we designed a multi-protected L-DOPA prodrugs able to release the drug by both spontaneous chemical or enzyme catalyzed hydrolysis.