ABSTRACT
Excessive stimulation of NMDA receptors is involved in various CNS pathologies such as Parkinson's disease, acute and chronic pain and cerebral ischaemia. The use of NMDA antagonists as therapeutic agents has been restricted as a result of unwanted side effects including hallucinations and loss of co-ordination. NR2B subtype selective antagonists have previously shown a therapeutic effect without causing the side effects of broad spectrum NMDA antagonists. Considerable research has since been devoted to the development of orally bioavailable, selective NR2B antagonists and their applications in various neurological diseases. The improved therapeutic index of these compounds is expected to be the result of the subtype selectivity and cellular location of the NR2B receptors within the CNS. This review describes recent advances in the development of NR2B antagonists as well as their therapeutic applications.
Subject(s)
Benzamidines/chemical synthesis , Benzamidines/therapeutic use , Excitatory Amino Acid Antagonists , Piperidines/chemical synthesis , Piperidines/therapeutic use , Receptors, N-Methyl-D-Aspartate , Animals , Brain Ischemia/drug therapy , Chemistry, Pharmaceutical , Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Humans , Mice , Pain/drug therapy , Parkinson Disease/drug therapy , Rats , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/physiology , Structure-Activity RelationshipSubject(s)
Calcium-Binding Proteins/biosynthesis , Calcium-Binding Proteins/genetics , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/physiopathology , Gene Expression Regulation, Developmental , Islets of Langerhans/pathology , Islets of Langerhans/physiopathology , Nerve Tissue Proteins , Aging , Animals , Diabetes Mellitus, Type 1/genetics , Disease Susceptibility , Immunity, Innate , Islets of Langerhans/growth & development , Lithostathine , Phosphoproteins/genetics , Phosphoproteins/physiology , Proinsulin/biosynthesis , RNA, Messenger/biosynthesis , Rats , Rats, Inbred BB , Transcription, GeneticSubject(s)
Diabetes Mellitus, Type 1/physiopathology , Gene Expression , Islets of Langerhans/physiopathology , Pancreas/physiopathology , Regeneration/genetics , Animals , Diabetes Mellitus, Type 1/genetics , Humans , Insulin , Islets of Langerhans/physiology , Pancreas/physiology , Pancreatectomy , Proinsulin/biosynthesis , Protein Precursors/biosynthesis , Rats , Rats, Inbred BB/geneticsABSTRACT
Active cytomegalovirus (CMV) infection induces immunosuppression and predisposes to the development of life-threatening superinfections in immunocompromised patients. We have described a mouse model in which acute murine CMV (MCMV) infection reactivates previously dormant Toxoplasma gondii infection, manifested as pneumonia. To determine whether therapy with ganciclovir might prevent MCMV-induced reactivation of T. gondii pneumonia, we administered ganciclovir to mice starting 1 day before to 2 days after MCMV infection and continuing for 14 days. When ganciclovir was begun early (before, on the day of, or 1 day after MCMV infection), the severity of T. gondii pneumonia reactivated by MCMV was significantly reduced. However, when therapy was delayed, no beneficial effect of ganciclovir was observed and the severity of MCMV-induced reactivation of T. gondii pneumonia was comparable to that seen in untreated animals. We conclude that ganciclovir therapy can attenuate but not eliminate MCMV-induced reactivation of T. gondii pneumonia and that prophylactic or very early administration of the drug is necessary to achieve protection.
Subject(s)
Ganciclovir/therapeutic use , Lung Diseases, Parasitic/drug therapy , Muromegalovirus/physiology , Pneumonia/drug therapy , Toxoplasmosis, Animal/drug therapy , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Ganciclovir/standards , Herpesviridae Infections/complications , Immunosuppression Therapy , Lung/microbiology , Lung/parasitology , Lung/pathology , Lung Diseases, Parasitic/etiology , Mice , Mice, Inbred BALB C , Muromegalovirus/isolation & purification , Pneumonia/etiology , Pneumonia/parasitology , Severity of Illness Index , Time Factors , Toxoplasma/isolation & purification , Toxoplasma/physiology , Toxoplasmosis, Animal/etiology , Virus Activation/drug effectsABSTRACT
A method of regenerating cotton plants from the shoot apical meristem of seedlings was developed for use with particle gun and Agrobacterium-mediated transformation. This method was developed to circumvent the problems of genotype restriction and chromosomal damage frequently encountered in cotton regeneration in tissue culture through somatic embryogenesis. In this procedure, the cells of the shoot meristem are targeted for transformation. Normal and fertile plants of Gossypium barbadense Pima S-6, and 19 cultivars of G. hirsutum were regenerated using this method. Shoot regeneration from these tissues was direct and relatively rapid. A MS based, hormone-free medium could be used with all the varieties tested.
ABSTRACT
The structure of bovine heart mitochondrial NADH dehydrogenase was investigated by using two cleavable cross-linking agents, disuccinimidyl tartrate and (ethylene glycol)yl bis-(succinimidyl succinate). Cross-linking was analysed primarily by immunoblotting to detect products containing subunits of the iron-protein fraction from chaotropic resolution of the enzyme, namely those of 75, 49, 30 and 13 kDa. By using both the isolated iron-protein fraction and the intact dehydrogenase, cross-links were identified between these four subunits, from these subunits to the largest subunit of the flavoprotein fraction, which contains the active site for NADH, and from these subunits to polypeptides in the hydrophobic shell, which surrounds the hydrophilic iron-protein and flavoprotein fractions.
