Neurotrophic factors, reductions

A typical second step after the insertion of CO into aryl or alkenyl-Pd(II) compounds is the addition to alkenes [148]. However, allenes can also be used (as shown in the following examples) where a it-allyl-r 3-Pd-complex is formed as an intermediate which undergoes a nucleophilic substitution. Thus, Alper and coworkers [148], as well as Grigg and coworkers [149], described a Pd-catalyzed transformation of o-iodophenols and o-iodoanilines with allenes in the presence of CO. Reaction of 6/1-310 or 6/1-311 with 6/1-312 in the presence of Pd° under a CO atmosphere (1 atm) led to the chromanones 6/1-314 and quinolones 6/1-315, respectively, via the Jt-allyl-r 3-Pd-complex 6/1-313 (Scheme 6/1.82). The enones obtained can be transformed by a Michael addition with amines, followed by reduction to give y-amino alcohols. Quinolones and chromanones are of interest due to their pronounced biological activity as antibacterials [150], antifungals [151] and neurotrophic factors [152]. 

In animal studies, high levels of cortisol have been shown to induce (increase) the activity of the enzyme tryptophan 2,3-dioxygenase in the liver, thereby decreasing the bioavailability of tryptophan to the brain. It is interesting to note that low acute doses of a number of different antidepressants inhibit the activity of this enzyme and, as a result, increase brain tryptophan concentrations, thus stimulating 5-HT synthesis (Badawy and Evans, 1982). In this way a link between the two key monoamine neurotransmitters and the hormone may be seen namely, reduced brain NA activity leads to decreased inhibition of the HPA axis, while increased levels of cortisol reduce 5-HT activity in the brain. Activation of the HPA axis has also been shown to result in tissue atrophy, in particular of the limbic system s hippocampus, and a reduction in the levels of neurotrophic factors responsible for the maintenance and optimal function of brain neurons (Manji et al., 2001). In conclusion, manipulation of the HPA axis (Nemeroff, 2002) and stimulation of neurotrophic factor activity (Manji et al., 2001) might open up new avenues for the treatment of affective disorders. 

Ischaemic stroke is the third leading cause of death in industrialized countries. The debilitating or lethal consequences of transient or temporary reductions in cerebral blood flow are not only caused by necrosis in the infarct zone itself, but also by pathophysiological events in the peri-infarct zone [14]. Apparently, the release of inflammatory mediators such as cytokines and NO contributes to tissue inflammatory injury. There is also evidence for apoptosis in the peri-infarct zone. These processes offer novel targets for therapeutic strategies. In this respect, the potential of neurotrophic factor treatment is described in Section 2.4.2.6. 

Selective Reduction of the Intermolecular Disulfide Bridge in Human Glial Cell Line-Derived Neurotrophic Factor Using Tris-(2-Carboxyethyl)Phosphine... 

Miyoshi Y, Zhang Z, Ovadia A, Lapchak PA, Collins F, Hilt D, Lebel C, Kryscio R, Gash DM (1997) Glial cell line derived neurotrophic factor-levodopa interactions and reduction of side effects in parkinsonian monkeys. Ann Neurol 42 208-214. 

Oppenheim, R.W., Haverkamp, L.J., Prevette, D., McMana-man, J.L. and Appel, S.H. (1988) Reduction of naturally occurring motoneuron death in vivo by a target-derived neurotrophic factor. Science 240 919-922. 

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