PMC:4536246 / 2471-4628 JSONTXT

{"project":"TEST0","denotations":[{"id":"26272684-161-166-1511535","span":{"begin":161,"end":162},"obj":"[\"7641257\"]"},{"id":"26272684-118-123-1511536","span":{"begin":438,"end":439},"obj":"[\"1347093\"]"},{"id":"26272684-121-126-1511537","span":{"begin":441,"end":442},"obj":"[\"7515129\"]"},{"id":"26272684-200-205-1511538","span":{"begin":868,"end":869},"obj":"[\"9701046\"]"},{"id":"26272684-203-208-1511539","span":{"begin":871,"end":872},"obj":"[\"10922458\"]"},{"id":"26272684-136-141-1511540","span":{"begin":1011,"end":1012},"obj":"[\"1347093\"]"},{"id":"26272684-133-138-1511541","span":{"begin":1148,"end":1149},"obj":"[\"15105281\"]"},{"id":"26272684-49-54-1511542","span":{"begin":1334,"end":1335},"obj":"[\"15105281\"]"},{"id":"26272684-52-57-1511543","span":{"begin":1337,"end":1338},"obj":"[\"14553822\"]"},{"id":"26272684-215-220-1511544","span":{"begin":1500,"end":1501},"obj":"[\"10092643\"]"},{"id":"26272684-209-215-1511545","span":{"begin":1713,"end":1715},"obj":"[\"15197741\", \"25499850\"]"},{"id":"26272684-83-88-1511546","span":{"begin":1905,"end":1906},"obj":"[\"10092643\"]"},{"id":"26272684-86-92-1511547","span":{"begin":1908,"end":1910},"obj":"[\"25499850\"]"},{"id":"26272684-148-154-1511548","span":{"begin":1970,"end":1972},"obj":"[\"17202769\"]"},{"id":"26272684-93-99-1511549","span":{"begin":2072,"end":2074},"obj":"[\"21359872\", \"19282179\", \"19673897\"]"}],"text":"Nitric oxide (NO) may function as a signaling molecule in controlling neuronal activity and plays an important role in governing sensory inputs during migraine [1]. Endogenous NO is produced by the constitutive isoforms of NO synthase, endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS). Asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of NOS, inhibits NO production in vivo and in vitro [2, 3]. Besides ADMA, two other forms of methylated arginine — which can be considered arginine analogues — have been identified in eukaryotes: NG-monomethyl-l-arginine (l-NMMA), and ω-NG,N′G-symmetric dimethylarginine (SDMA) [4]. All three methylated arginines (ADMA, l-NMMA and SDMA) are inhibitors of arginine transport at superphysiological concentrations, while the physiological relevance of this inhibition remains unclear [5, 6]. Circulating ADMA is present at higher concentrations than l-NMMA and is often considered to be the principal inhibitor of NOS activity [2]. Most of ADMA is degraded by dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine [7]. Therefore, this enzymatic pathway is a potential endogenous mechanism for the regulation of NO production by competitive inhibition. ADMA has been associated to cardiovascular risk [7, 8] as it seems involved in the development and progression of cardiovascular disease, via the inhibition of eNOS activity and increased production of superoxides [9]. However, high levels of ADMA and increased DDAH-1 expression have been detected in the brain, and spinal cord, thus suggesting a possible role for the ADMA-DDAH pathway in the modulation of neuronal activity [10–12]. This hypothesis seems even more compelling when considering that DDAH-1 co-localizes with nNOS [11]. Increased ADMA levels seem to induce endothelial dysfunction and oxidative stress [9, 12], two potential factors involved in migraine pathogenesis [13, 14]. Available data on ADMA plasma levels and migraine have yielded inconclusive findings so far [15–17] and there is no information on ADMA/DDAH pathway in animal models of migraine."}

{"project":"2_test","denotations":[{"id":"26272684-7641257-60565563","span":{"begin":161,"end":162},"obj":"7641257"},{"id":"26272684-1347093-60565564","span":{"begin":438,"end":439},"obj":"1347093"},{"id":"26272684-7515129-60565565","span":{"begin":441,"end":442},"obj":"7515129"},{"id":"26272684-9701046-60565566","span":{"begin":868,"end":869},"obj":"9701046"},{"id":"26272684-10922458-60565567","span":{"begin":871,"end":872},"obj":"10922458"},{"id":"26272684-1347093-60565568","span":{"begin":1011,"end":1012},"obj":"1347093"},{"id":"26272684-15105281-60565569","span":{"begin":1148,"end":1149},"obj":"15105281"},{"id":"26272684-15105281-60565570","span":{"begin":1334,"end":1335},"obj":"15105281"},{"id":"26272684-14553822-60565571","span":{"begin":1337,"end":1338},"obj":"14553822"},{"id":"26272684-10092643-60565572","span":{"begin":1500,"end":1501},"obj":"10092643"},{"id":"26272684-15197741-60565573","span":{"begin":1713,"end":1715},"obj":"15197741"},{"id":"26272684-25499850-60565573","span":{"begin":1713,"end":1715},"obj":"25499850"},{"id":"26272684-10092643-60565574","span":{"begin":1905,"end":1906},"obj":"10092643"},{"id":"26272684-25499850-60565575","span":{"begin":1908,"end":1910},"obj":"25499850"},{"id":"26272684-17202769-60565576","span":{"begin":1970,"end":1972},"obj":"17202769"},{"id":"26272684-21359872-60565577","span":{"begin":2072,"end":2074},"obj":"21359872"},{"id":"26272684-19282179-60565577","span":{"begin":2072,"end":2074},"obj":"19282179"},{"id":"26272684-19673897-60565577","span":{"begin":2072,"end":2074},"obj":"19673897"}],"text":"Nitric oxide (NO) may function as a signaling molecule in controlling neuronal activity and plays an important role in governing sensory inputs during migraine [1]. Endogenous NO is produced by the constitutive isoforms of NO synthase, endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS). Asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of NOS, inhibits NO production in vivo and in vitro [2, 3]. Besides ADMA, two other forms of methylated arginine — which can be considered arginine analogues — have been identified in eukaryotes: NG-monomethyl-l-arginine (l-NMMA), and ω-NG,N′G-symmetric dimethylarginine (SDMA) [4]. All three methylated arginines (ADMA, l-NMMA and SDMA) are inhibitors of arginine transport at superphysiological concentrations, while the physiological relevance of this inhibition remains unclear [5, 6]. Circulating ADMA is present at higher concentrations than l-NMMA and is often considered to be the principal inhibitor of NOS activity [2]. Most of ADMA is degraded by dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine [7]. Therefore, this enzymatic pathway is a potential endogenous mechanism for the regulation of NO production by competitive inhibition. ADMA has been associated to cardiovascular risk [7, 8] as it seems involved in the development and progression of cardiovascular disease, via the inhibition of eNOS activity and increased production of superoxides [9]. However, high levels of ADMA and increased DDAH-1 expression have been detected in the brain, and spinal cord, thus suggesting a possible role for the ADMA-DDAH pathway in the modulation of neuronal activity [10–12]. This hypothesis seems even more compelling when considering that DDAH-1 co-localizes with nNOS [11]. Increased ADMA levels seem to induce endothelial dysfunction and oxidative stress [9, 12], two potential factors involved in migraine pathogenesis [13, 14]. Available data on ADMA plasma levels and migraine have yielded inconclusive findings so far [15–17] and there is no information on ADMA/DDAH pathway in animal models of migraine."}