The ex vivo tissue concentration of nitrite and nitrate (NO~) was found to correlate closely with the activity of nitric oxide synthase (NOS; EC 1.14.13.39) in various brain regions. Systemic administration of the nonselective NOS inhibitor N'~-nitro-L-arginine(L-NA) at doses that completely inhibited both central and peripheral NOS, depleted whole-brain and CSF NO. by up to 75% but had no effect on plasma NOR. Selective inhibition of central NOS by intracerebroventricular administration of L-NA methyl ester produced similar decreases in levels of whole-brain NOR. A residual concentration of NO. of 10-15 ,uM remained in all brain regions even after complete inhibition of brain NOS. Brain NO~content decreased rapidly and in parallel with the inhibition of brain NOS. The ex vivo measurement of levels of brain NO. was found to reflect the in vivo efficacy of several different types of NOS inhibitor: L-NA, N~-monomethyl-L-arginine, and 7-nitroindazole. Intraperitoneal administration of the NOS substrate L-arginine increased brain NO. concentrations by up to 150% of control values. These results demonstrate that the ex vivo measurement of levels of brain tissue NO~is a rapid, reliable, and straightforward technique to determine NOS activity in vivo. This method can be used to assess both the regional distribution and the degree of inhibition of NOS activity in vivo. Key Words: Nitric oxide synthase-Nitrite-Nitrate-N~-Nitro-L-arginine-N~-Monomethyl-L-arginine-7-Nitroindazole. oxide; NOS, nitric oxide synthase; NO,, nitrite and nitrate.
Selective inhibition of the neuronal isoform of nitric oxide synthase (NOS) compared to the endothelial and inducible isoforms may be required for treatment of neurological disorders caused by excessive production of nitric oxide. Recently, we described N-(3-(aminomethyl)benzyl)acetamidine (13) as a slow, tight-binding inhibitor, highly selective for human inducible nitric oxide synthase (iNOS). Removal of a single methylene bridge between the amidine nitrogen and phenyl ring to give N-(3-(aminomethyl)phenyl)acetamidine (14) dramatically altered the selectivity to give a neuronal selective nitric oxide synthase (nNOS) inhibitor. Part of this large shift in selectivity was due to 14 being a rapidly reversible inhibitor of iNOS in contrast to the essentially irreversible inhibition of iNOS observed with 13. Structure-activity studies revealed that a basic amine functionality tethered to an aromatic ring and a sterically compact amidine are key pharmacophores for this class of NOS inhibitors. Maximal nNOS inhibition potency was achieved with N-(3-(aminomethyl)phenyl)-2-furanylamidine (77) (Ki-nNOS = 0.006 microM; Ki-eNOS = 0.35 microM; Ki-iNOS = 0.16 microM). Finally, alpha-fluoro-N-(3-(aminomethyl)phenyl)acetamidine (74) (Ki-nNOS = 0. 011 microM; Ki-eNOS = 1.1 microM; Ki-iNOS = 0.48 microM) had excellent brain penetration and inhibited nNOS in a rat brain slice assay as well as in the rat brain (cerebellum) in vivo. Thus, N-phenylamidines should be useful in validating the role of nNOS in neurological disorders.
Agroforestry has potential for strengthening the climate change resilience of smallholder farmers in Southeast Asia. In Indonesia, the food security challenges faced by smallholders will likely worsen due to climate change impacts. Agroforestry provides and option for strengthening climate change resilience, while contributing to food access, income, health, and environmental stability. To evaluate the evidence for such benefits, this systematic review identifies 22 peer-reviewed articles published between 2000 and 2019 which assess agroforestry’s contributions to food security in Indonesia, mostly in Java or Sumatra. Analysis of the studies indicate that traditional and commercial agroforestry contribute to food security in diverse ways: for example, traditional homegardens offer 20% more dietary diversity than commercial counterparts, while commercial homegardens may contribute up to five times more income. Agri-silviculture contributions fall along a timber versus non-timber forest product continuum that displays a similar tradeoff between diversity and income. Those systems with a commercial focus may receive 54% of their income from a single commodity crop such as coffee, while traditional systems allow greater access to plants with medicinal benefits. Nearly all agroforestry systems offered indirect benefits for food security, such as allowing more off-farm work than traditional agriculture and contributing to environmental stability: users of agroforestry were found by one study to collect 83% less fuelwood from natural forests. One study highlighted that agroforestry options have up to 98% greater net present value (for periods over 30 years) compared to slash and burn style agriculture. However, very few studies of Indonesian agroforestry focused explicitly on financial analysis and food security, indicating the need for further research. Given the similar situations faced by many Southeast Asia countries, our findings contribute to emerging trends throughout the region regarding the relationship between agroforestry and food security.
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