A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately 1.2 ± 0.4 h and 1.4 ± 0.5 h, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of 31.5 ± 5.7% was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at 46.5 ± 3.5 ng/g in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, 46.5 ± 3.5 ng/g donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.
Acetylcholinesterase* ; Animals ; Biological Availability ; Brain ; Humans ; Learning* ; Memory* ; Mice ; Plasma ; Rats, Hairless ; Rodentia*

BACKGROUND: During normal wound healing the formation of scars and fibrous tissue occurs, which consists largely of collagen fibril, but excessive fibrosis and scar formation become clinical problems. Collagen remodelling during scar formation is dependent on both continued collagen synthesis and collagen catabolism. Halofuginone, a plant alkaloid, is known to inhibit collagen type I synthesis at the transcriptional level. OBJECTIVE: The purposes of this study were to investigate the effects of topical application of halofuginone on the healing of wounds. METHOD: Topical solutions containing halofuginone of variable concentrations were applied on the full-thickness excisional wounds of hairless mice and 0.1% halofuginone ointments applied on the suture site of rats and the normal skin of hairless mice daily. In addition, we performed a one-time intradermal injection of 0.1% halofuginone solution on the normal skin of the hairless mice. We examined the collagen content of the skin of hairless mice and rats treated with halofuginone solutions and ointments during the healing process by performing hematoxylin-eosin and Masson's trichrome stains. We assessed, from time to time, the change in the full-thickness excisional wound size of hairless mice treated with halofuginone solutions of variable concentrations during the healing process and observed clinically the healing process of hairless mice with the full-thickness excisional wound. RESULT: 1. The wound size after daily application of 0.001% and 0.1% halofuginone solutions on the full-thickness excisional wounds of hairless mice decreased more slowly in comparison with the control group (p < 0.05).
Animals ; Cicatrix ; Collagen ; Collagen Type I ; Coloring Agents ; Fibrosis ; Injections, Intradermal ; Metabolism ; Mice ; Mice, Hairless ; Ointments ; Plants ; Rats ; Skin ; Sutures ; Wound Healing* ; Wounds and Injuries*

BACKGROUND: The treatment of facial rhytides has traditionally centered around methods that involve removal of the epidermis and superficial dermis, encouraging the production of a new epidermis with collagenesis and remodelling. But all of the resurfacing techniques lead to postoperative complications such as oozing, bleeding, infections, "downtime" as the skin begins to reepithelialize, and the occasional incidence of posttreatment, postinflammatory pigmentary changes. 1320nm and 1064nm wavelengths are nonspecifically absorbed in the human dermis and are unique for its significant horizontal scattering. These wavelengths, when used for localized facial areas, have been shown to produce new collagen formation and improvement in the quality of treated skin. OBJECTIVE: The purpose of this study was to examine the effect of 1320nm Nd: YAG laser and long-pulsed 1064nm Nd: YAG laser irradiation on hairless mouse skin and rat skin. METHODS: In this study, the effect of 1320nm Nd: YAG laser and long-pulsed 1064nm Nd: YAG laser irradiation were examined by Hematoxylin and eosin (H&E) stain, Masson's trichrome stain, immunohistochemical stain for type I collagen and dot-blot hybridization for alpha1(I) procollagen mRNA. RESULTS: In the H&E stain, Masson's trichrome stain, and immunohistochemical stain of the hairless mouse skin, the number of collagen fibers with a greater density of fibers increased, compared to the non-irradiated controls on both the 1320nm Nd: YAG laser and the long-pulsed 1064nm Nd: YAG laser. In the dot-blot hybridization in the hairless mouse, levels of alpha1(I) procollagen mRNA were increased 3.0-fold, 4.8-fold and 5.2-fold at each 1 week, 4 weeks and 12 weeks after irradiation in 1320nm Nd: YAG laser and 1.8-fold and 2.1-fold at each 4 weeks and 12 weeks after irradiation in long-pulsed 1064nm Nd: YAG laser, compared to the non-irradiated controls. But in the 1320nm Nd: YAG laser irradiation on the rat, there is no significant change in the number and density of collagen fibers, compared to the non- irradiated controls. CONCLUSION: These results indicate that the 1320nm Nd: YAG laser and the long-pulsed 1064nm Nd: YAG laser may be a powerful up-regulator of collagen synthesis through significant dermal damage and the 1320nm Nd: YAG laser is better than the long-pulsed 1064nm Nd: YAG laser for collagen synthesis. Therefore, the 1320nm Nd: YAG laser can be more effective clinically than the long-pulsed 1064nm Nd: YAG laser for the treatment of photodamaged skin.
Animals ; Collagen ; Collagen Type I ; Dermis ; Eosine Yellowish-(YS) ; Epidermis ; Hematoxylin ; Hemorrhage ; Humans ; Incidence ; Lasers, Solid-State* ; Mice ; Mice, Hairless* ; Postoperative Complications ; Procollagen ; Rats ; RNA, Messenger ; Skin*