Using the above neonatal hypoxicCischemic procedure, the rat pups were treated with 500 mg/kg of nicotinamide by i.p. 7 pg/g in the shams (= 6), 175 17 pg/g in the 500 mg/kg nicotinamide treated (= 7), and 320 79 pg/g in the vehicle treated pups (= 7, 0.05 versus sham, 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia ( 0.01). Nicotinamide reduces brain injury in the neonatal rat, probably by Tiagabine reducing oxidative stress and caspase-3 activity. launch and caspase-3 and caspase-9 like activities [10]. In adult animals nicotinamide protects against free radical injury to the brain [10,23,29]. Oxidants and free radicals can initiate apoptosis by stimulating mitochondrial pore formation [35]. Oxidants and free radicals can cause solitary stranded DNA breaks, which can activate poly(ADP-ribose) polymerase [5,12]. Treatments with nicotinamide are neuroprotective in adult rat transient cerebral ischemia [4,28,41] and long term focal cerebral ischemia [3,34]. Nicotinamide is also effective in adult rats even when given 6 h after injury [4,41]. Does nicotinamide have related pharmacological effects and neuroprotective effects in newborn animals to that seen in adult animal? These questions have not been properly resolved. HypoxicCischemic injury is an important cause of death and disability in newborn humans. The developmental stage of the brain of the 7-day-old rat pup resembles that of term newborn humans [31]. Therefore, study of the part of neuroprotective providers in the neonatal hypoxicCischemic rat model may provide important information relevant to the development of treatment for perinatal hypoxicCischemic mind damage. The neonatal rat hypoxicCischemic model [32] has been well characterized and extensively used to assess synthetic neuroprotective providers (for review, observe [1,2]). Clinical mind injury is definitely caused by hypoxia or ischemia rather than the combination. However, hypoxia of a clinically relevant severity will cause ischemia by inhibiting heart function. Cellular hypoxia is the end point of both hypoxia and ischemia. The ischemia in the Rice model does not cause damage unless combined with hypoxia [32]. In addition, the long-term survival of rats from Tiagabine your Rice model allows study of extremely important late effect [39]. We have used this hypoxicCischemic model to evaluate the neuroprotective potency of several medicines [13C15]. The purpose of the present study was to determine whether treatment with nicotinamide would reduce brain injury in newborn rats and to evaluate the effects of nicotinamide on oxygen free radicals and caspase-3 by using the neonatal rat hypoxic ischemic model. This has not previously been tested. 2. Materials and methods 2.1. Animal protocol and drug treatment Our institutional committee on animal use authorized this protocol. Rats were cared for in accordance with the National Institute of Health recommendations. Seven-day-old SpragueCDawley rats (Harlan SpragueCDawley, Indianapolis, IN) weighing 12C17 g of either sex were anesthetized with isoflurane and experienced the right common carotid artery isolated from your nerve and vein, and permanently doubly ligated. The wound was infiltrated with marcaine, a long acting local anesthetic, at the end of the surgery treatment to prevent postoperative pain. The whole process took less than 7 min. The pups were returned to their dam for at least 3 h recovery after surgery. The pups were then placed in sealed jars inside a 37 C water bath and subjected to a warmed, humidified mix of 8% oxygen and 92% nitrogen delivered at 4 l/min for 2.5 h. To assess the neuroprotective effect of nicotinamide, pups were randomized to treatment with 500 mg/kg nicotinamide (= 29), or vehicle (saline, = 28); or 250 mg/kg nicotinamide (= 22), or vehicle (saline, = 23) i.p. immediately after the hypoxia with a second identical dose given 6 h later on. The dose was chosen from your adult rat literature [3,4,17,28,34]. To keep up brain concentration we chose to inject a second identical dose of nicotinamide at 6 h after the first injection. Pups were returned to their dams and allowed to recover and grow for 22 days. They were weighed prior to injury and again at 4, 7, 11, 14 and 22 days after injury. Rectal heat was taken having a 36 gauge flexible thermocouple (Omega Executive Inc., Stamford, CT, USA) inside a sub-set of these pups (five treated with 500 mg/kg of nicotinomide and five from your corresponding vehicle group) prior to dosing and at 0.13, 0.25 0.5, 0.75, 1, 2, 3, 4 and 6 h after treatment. In order to standardize the measurement and reduce the variance, heat measurements were taken 15 min after removal from your nest into a 25 C space. 2.2. Gross mind damage grading Rat pups were anesthetized with pentobarbital and decapitated 22 days after hypoxic exposure. The brains were removed, obtained and weighed by an observer blind to the code..Our present data confirm their effects. treated (= 7), and 320 79 pg/g in the vehicle treated pups (= 7, 0.05 versus sham, 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia ( 0.01). Nicotinamide reduces brain injury in the neonatal rat, probably by reducing oxidative stress and caspase-3 activity. launch and caspase-3 and caspase-9 like activities [10]. In adult animals nicotinamide protects against free radical injury to the brain [10,23,29]. Oxidants and Tiagabine free radicals can initiate apoptosis by stimulating mitochondrial pore formation [35]. Oxidants and free radicals can cause solitary stranded DNA breaks, which can activate poly(ADP-ribose) polymerase [5,12]. Treatments with nicotinamide are neuroprotective in adult rat transient cerebral ischemia [4,28,41] and long term focal cerebral ischemia [3,34]. Nicotinamide is also effective in adult rats even when given 6 h after injury [4,41]. Does nicotinamide have related pharmacological effects and neuroprotective effects in newborn animals to that seen in adult animal? These questions have not been adequately resolved. HypoxicCischemic injury is an important cause of death and disability in newborn humans. The developmental stage of the brain of the 7-day-old rat pup resembles that of term newborn humans [31]. Therefore, study of the part of neuroprotective providers in the neonatal hypoxicCischemic rat model may provide important information relevant to the development of treatment for perinatal hypoxicCischemic mind damage. The neonatal rat hypoxicCischemic model [32] has been well characterized and extensively used to assess synthetic neuroprotective providers (for review, observe [1,2]). Clinical mind injury is caused by hypoxia or ischemia rather than the combination. However, hypoxia of a clinically relevant severity will cause ischemia by inhibiting heart function. Cellular hypoxia is the end point of both hypoxia and ischemia. The ischemia in the Rice model does not cause damage unless combined with hypoxia [32]. In addition, the long-term survival of rats from your Rice model allows study of extremely important late effect [39]. We have used this hypoxicCischemic model to evaluate the neuroprotective potency of several medicines [13C15]. The purpose of the present study was to determine whether treatment with nicotinamide would reduce brain injury in newborn rats and to evaluate the effects of nicotinamide on oxygen free radicals and caspase-3 by using the neonatal rat hypoxic ischemic model. This has not previously been tested. 2. Materials and methods 2.1. Animal protocol and drug treatment Our institutional committee on animal use authorized this protocol. Rats were cared for in accordance with the National Institute of Health recommendations. Seven-day-old SpragueCDawley rats (Harlan SpragueCDawley, Indianapolis, IN) weighing 12C17 g of either sex were anesthetized with isoflurane and experienced the right common carotid artery isolated from Tiagabine your nerve and vein, and permanently doubly ligated. The wound was infiltrated with marcaine, a long acting local anesthetic, at the end of the surgery to prevent postoperative pain. The whole procedure took less than 7 min. The pups were returned to their dam for at least 3 h recovery after surgery. The pups were then placed in sealed jars inside a 37 C water bath and subjected to a warmed, humidified mix of 8% oxygen and 92% nitrogen delivered at 4 l/min for 2.5 h. To assess the neuroprotective effect of nicotinamide, pups were randomized to treatment with 500 mg/kg nicotinamide (= 29), or vehicle (saline, = 28); or 250 mg/kg nicotinamide (= 22), or vehicle (saline, = 23) i.p. immediately after the hypoxia with a second identical dose given 6 h later on. The dose was chosen from your adult rat literature [3,4,17,28,34]. To keep up brain concentration we chose to inject a second identical dose of nicotinamide at 6 h after the first injection. Pups were returned to their dams and allowed to recover and grow for 22 days. They were weighed prior to injury and again at 4, 7, 11, 14 and Slc2a4 22 days after injury. Rectal heat was taken.
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