Interaction of alpha-synuclein with lipids.

Alpha-synuclein (α-syn) is a natively unfolded protein that is abundantly expressed in the central nervous system. Although it has been shown to be involved in neurotransmission and cognition, its exact functions remain elusive. The misfolding of this protein into β-sheet-rich amyloid structures and subsequent aggregation has been associated with several neurodegenerative diseases, including Parkinson's disease.

Are ion channels potential therapeutic targets for Parkinson's disease?

Parkinson's disease (PD) is primarily associated with the progressive neurodegeneration of the dopaminergic neurons in the substantia nigra region of the brain. The resulting motor symptoms are managed with the help of dopamine replacement therapies. However, these therapeutics do not prevent the neurodegeneration underlying the disease and therefore lose their effectiveness in managing disease symptoms over time.

Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling.

Poorly soluble weak bases form a significant proportion of the drugs available in the market thereby making it imperative to understand their absorption behavior. This work aims to mechanistically understand the oral absorption behavior for a weakly basic drug, Irbesartan (IRB), by investigating its pH dependent solubility, supersaturation, and precipitation behavior. Simulations performed using the equilibrium solubility could not accurately predict oral absorption.

Role of Surface Characteristics of Mannitol in Crystallization of Fenofibrate During Spray Drying.

NanoCrySP™ is a novel spray-drying-based technology for the generation of nanocrystalline solid dispersions of active pharmaceutical ingredients embedded in the matrix of small molecule excipients. Active pharmaceutical ingredient first appears as an amorphous phase, which transforms to crystalline phase during its passage in the drying chamber. Mannitol acts as a crystallization inducer for the intermediate amorphous phase by primary heterogeneous nucleation.

α-Synuclein 2.0 - Moving towards Cell Type Specific Pathophysiology.

Since the landmark discovery that point mutations in the α-synuclein gene (SNCA) cause familial Parkinson's disease (PD) more than 2 decades ago, extensive research has been conducted to unravel the molecular and cellular mechanisms by which α-synuclein drives PD pathogenesis resulting in selective neurodegeneration of vulnerable neuronal populations. Current interest focuses on the identification of relevant toxic α-synuclein conformers and their interaction with basic cellular functions. In this context, seminal advances have been made in defining mechanisms of α-synuclein's toxicity in neurons, but many open questions remain regarding its neuronal subtype pathophysiology, as well as the defining the most disease relevant conformations.

Assessment of Biopharmaceutical Performance of Supersaturating Formulations of Carbamazepine in Rats Using Physiologically Based Pharmacokinetic Modeling.

There is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ).

Permeability Behavior of Nanocrystalline Solid Dispersion of Dipyridamole Generated Using NanoCrySP Technology.

Nanocrystals research has been an area of significant interest lately, providing oral bioavailability benefits to solubility- and/or dissolution rate-limited drugs. Drug nanocrystals are generated using top-down or bottom-up technologies. Combination technologies (Nanoedge, Nanopure XP and SmartCrystal) have been recently developed to generate nanocrystals of improved properties.

Modeling Parkinson's disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain.

Although a causative role of α-synuclein (α-syn) is well established in Parkinson's disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson's disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration. We show that the ability of human α-syn fibrils to trigger Lewy-like α-synuclein pathology in the affected DA neurons is dramatically enhanced in the presence of elevated levels of human α-syn.

Investigation of Need of Natural Bioenhancer for a Metabolism Susceptible Drug-Raloxifene, in a Designed Self-Emulsifying Drug Delivery System.

Bioenhancers can increase the bioavailability of metabolism susceptible drugs. The present study was designed to understand the impact of bioenhancer on permeability and bioavailability of a biopharmaceutical drug disposition classification system (BDDCS) class II drug raloxifene (RLX). RLX undergoes extensive first pass metabolism by UGT enzymes in gastrointestinal tract (GIT) and has an oral bioavailability of about 2%.

Inhibition of neuroinflammation and mitochondrial dysfunctions by carbenoxolone in the rotenone model of Parkinson's disease.

α-Synuclein aggregation contributes to the Parkinson's disease (PD) pathology in multiple ways-the two most important being the activation of neuroinflammation and mitochondrial dysfunction. Our recent studies have shown the beneficial effects of a heat shock protein (HSP) inducer, carbenoxolone (Cbx), in reducing the aggregation of α-synuclein in a rotenone-based rat model of PD. The present study was designed to explore its ability to attenuate the α-synuclein-mediated alterations in neuroinflammation and mitochondrial functions.

Modulatory effects of sodium salicylate on the factors affecting protein aggregation during rotenone induced Parkinson's disease pathology.

Sodium salicylate (SS) confers neuroprotection in various models of Parkinson's disease (PD) but the mechanisms behind its protective actions are not clear. PD pathology is multifactorial involving numerous processes such as protein aggregation, dysfunction of protein degradation machinery and apoptosis. Detailed evaluation of effects of SS on these processes can provide an insight into the mechanism of neuroprotection by SS in PD pathology.

Long-term heat shock proteins (HSPs) induction by carbenoxolone improves hallmark features of Parkinson's disease in a rotenone-based model.

Protein aggregation and dysfunction of ubiquitin proteasome system (UPS) have been implicated in Parkinson's disease (PD) pathology for a long time. Heat shock proteins (HSPs) have neuro-protective effects in PD as they assist in protein refolding and targeting of irreparable proteins to UPS. To realize their benefits in a chronically progressing disease like PD, it is imperative to maintain slightly up-regulated levels of HSPs consistently over a longer period of time.

Chemopreventive action of diclofenac in dimethybenzanthracene induced lung cancer in female Wistar rat.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective antineoplastic agents that block prostaglandin formation by inhibiting the enzyme cyclooxygenase (COX), which exists in two isoforms, COX-1 and COX-2. COX-2 is over expressed in lung cancer. The present study evaluates the chemopreventive efficiency of diclofenac, which is a preferentially selective COX-2 inhibitor in lung cancer.

Induction of pulmonary carcinogenesis in Wistar rats by a single dose of 9, 10 dimethylbenz(a)anthracene (DMBA) and the chemopreventive role of diclofenac.

Objectives: To evaluate the chemopreventive efficacy of Diclofenac, a preferential cyclooxygenase-2 (COX-2) inhibiting non steroidal anti-inflammatory drug (NSAID) in the 9, 10 Dimethylbenz(a)anthracene (DMBA) induced experimental lung carcinogenesis.

Methods: Animals were divided into 4 groups. Control group received normal saline intratratracheally.