gingerol and Alzheimer-Disease

Phosphodiesterase 4 (PDE4), mainly present in immune, epithelial, and brain cells, represents a family of key enzymes for the degradation of cyclic adenosine monophosphate (cAMP), which modulates inflammatory response. In recent years, the inhibition of PDE4 has been proven to be an effective therapeutic strategy for the treatment of neurological disorders. PDE4D constitutes a high-interest therapeutic target primarily for the treatment of Alzheimer's disease, as it is highly involved in neuroinflammation, learning ability, and memory dysfunctions. In the present study, a thorough computational investigation consisting of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on the linear response approximation (LRA) method was performed to study dietary polyphenols as potential PDE4D inhibitors. The obtained results revealed that curcumin, 6-gingerol, capsaicin, and resveratrol represent potential PDE4D inhibitors; however, the predicted binding free energies of 6-gingerol, capsaicin, and resveratrol were less negative than in the case of curcumin, which exhibited the highest inhibitory potency in comparison with a positive control rolipram. Our results also revealed that the electrostatic component through hydrogen bonding represents the main driving force for the binding and inhibitory activity of curcumin, 6-gingerol, and resveratrol, while the van der Waals component through shape complementarity plays the most important role in capsaicin's inhibitory activity. All investigated compounds form hydrophobic interactions with residues Gln376 and Asn602 as well as hydrogen bonds with nearby residues Asp438, Met439, and Ser440. The binding mode of the studied natural compounds is consequently very similar; however, it significantly differs from the binding of known PDE4 inhibitors. The uncovered molecular inhibitory mechanisms of four investigated natural polyphenols, curcumin, 6-gingerol, capsaicin, and resveratrol, form the basis for the design of novel PDE4D inhibitors for the treatment of Alzheimer's disease with a potentially wider therapeutic window and fewer adverse side effects.

Topics: Alzheimer Disease; Capsaicin; Catechols; Curcumin; Cyclic Nucleotide Phosphodiesterases, Type 4; Fatty Alcohols; Humans; Molecular Dynamics Simulation; Polyphenols; Resveratrol

Gingerol is a major dietary compound that occurs in several plants belonging to the Zingiberaceae family. In the current study, the protective effect of gingerol on STZ-induced sporadic Alzheimer's disease (SAD) was determined. Gingerol was isolated from the seeds of Aframomum melegueta K. Schum and tested at doses of 10 and 20 mg/kgbwt for its possible effect on the SAD model in mice, using celecoxib (30 mg/kg bwt) as a reference standard. The curative effects of gingerol were assessed through measurement of β-amyloid (Aβ-42), α-, β- secretases, APH1a and COX-2 levels. In addition, improvement in the cognitive deficit in mice after treatment was confirmed using the water maze and Y-maze with intra-maze cues. Gingerol improved the cognitive and behavioral impairment and AD-like pathology in streptozotocin model mice. These beneficial effects occurred with an increase in α-secretase activity and a decrease in cerebral Aβ-42, β- secretase, APH1a activity and COX-2-linked neuro-inflammation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Catechols; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Enzyme Activation; Fatty Alcohols; Immunohistochemistry; Maze Learning; Mice; Protective Agents; Streptozocin

Ginger rhizome (Zingiber officinale) has been used for centuries to treat dementia in South Asia. This study was undertaken to possibly justify its use. A 70% aqueous/methanolic extract of dried ginger (Zo.Cr) was used. Zo.Cr tested positive for the presence of terpenoids, flavonoids, secondary amines, phenols, alkaloids and saponins. When tested on isolated rat stomach fundus, Zo.Cr showed a spasmogenic effect (0.03-5.00 mg mL(-1)); it relaxed the tissue at concentrations > or =5 mg mL(-1). The stimulant effect was resistant to blockade by hexamethonium and methysergide, but sensitive to atropine, indicating activity via muscarinic receptors. In atropinized (0.1 microM) preparations, Zo.Cr (0.3-3.0 mg mL(-1)) relaxed high K(+) (80 mM)-induced contractions, indicating Ca(++) antagonism in addition to the muscarinic effect. This possible Ca(++) antagonist activity was investigated in Ca(++)-free conditions, with the inhibitory effect of the extract tested against contractions induced by externally administered Ca(++). Zo.Cr (0.1-0.3 mg mL(-1)), similar to verapamil (0.03-0.10 microM), shifted the contractions induced by externally administered Ca(++) to the right, thus suggesting an inhibitory interaction between Zo.Cr and voltage-operated Ca(++) channels. Zo.Cr (0.1-3.0 microg mL(-1)) also potentiated acetylcholine peak responses in stomach fundus, similar to physostigmine, a cholinesterase inhibitor. Zo.Cr, in an in-vitro assay, showed specific inhibition of butyrylcholinesterase (BuChE) rather than acetylcholinesterase enzyme. Different pure compounds of ginger also showed spasmolytic activity in stomach fundus, with 6-gingerol being the most potent. 6-Gingerol also showed a specific anti-BuChE effect. This study shows a unique combination of muscarinic, possible Ca(++) antagonist and BuChE inhibitory activities of dried ginger, indicating its benefit in dementia, including Alzheimer's disease.

Topics: Acetylcholine; Alzheimer Disease; Animals; Atropine; Butyrylcholinesterase; Calcium; Calcium Channel Blockers; Catechols; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Fatty Alcohols; Gastric Fundus; In Vitro Techniques; Molecular Structure; Muscarinic Agonists; Parasympatholytics; Physostigmine; Plant Extracts; Rats; Rats, Sprague-Dawley; Rhizome; Verapamil; Zingiber officinale