Aquaporin-4 and brain edema.

Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury

Aquaporin water channels in the nervous system.

The aquaporins (AQPs) are plasma membrane water-transporting proteins. AQP4 is the principal member of this protein family in the CNS, where it is expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation. AQP1 is expressed in the choroid plexus, where it facilitates cerebrospinal fluid secretion, and in dorsal root ganglion neurons, where it tunes pain perception. The AQPs are potential drug targets for several neurological conditions. Astrocytoma cells strongly express AQP4, which may facilitate their infiltration into the brain, and the neuroinflammatory disease neuromyelitis optica is caused by AQP4-specific autoantibodies that produce complement-mediated astrocytic damage

Aquaporins: important but elusive drug targets.

The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators

Research Paper - Effect of sodium sulfadimethylpyrimidine on multiple forms of cytochrome P450 in chicken

OBJECTIVE: To study the effect of sodium sulfadimethylpyrimidine (SDMP) on different forms of CYP 450 enzymes induced by phenobarbital (CYP 2B1, 2B2 and 3A), isoniazid (CYP 2E1), benzo(a)pyrene (CYP 1A1), clotrimazole (CYP 3A), and clofibrate (CYP 4A). MATERIALS AND METHODS: Chickens (Hubbard, male) weighing 250-300 g were divided into 17 groups of six each. Five experimental sets were prepared containing three subgroups each to test five different inducers. Microsomes were isolated by calcium precipitation. The levels of electron transport components, CYP 450, cytochrome b5, and cytochrome c-reductase were determined using extinction coefficients. Activities of drug-metabolizing enzymes were assayed. RESULTS: All inducers (phenobarbital, isoniazid, benzo(a)pyrene, clotrimazole, and clofibrate) showed significant induction of mixed function oxidase in chicken. The SDMP treatment of inducer-pretreated chicken caused a significant decrease in electron transport components and activities of drug-metabolizing enzymes when compared with treatment of inducer alone. Phenobarbital, isoniazid, and benzo(a)pyrene treatments of SDMP-pretreated chicken showed no significant change in induction pattern, however, significant alterations were observed in the induction pattern of clotrimazole and clofibrate. CONCLUSION : Our studies suggest that CYP 2B1, 2B2, 3A; CYP 2E1; CYP 1A1; CYP 3A and CYP 4A are susceptible species of CYP 450 to SDMP and its metabolites. The SDMP also affected in the induction pattern of some of the inducers with respect to CYP 450 isoforms

Research Paper - Effect of sodium sulfadimethylpyrimidine on multiple forms of cytochrome P450 in chicken

OBJECTIVE: To study the effect of sodium sulfadimethylpyrimidine (SDMP) on different forms of CYP 450 enzymes induced by phenobarbital (CYP 2B1, 2B2 and 3A), isoniazid (CYP 2E1), benzo(a)pyrene (CYP 1A1), clotrimazole (CYP 3A), and clofibrate (CYP 4A). MATERIALS AND METHODS: Chickens (Hubbard, male) weighing 250-300 g were divided into 17 groups of six each. Five experimental sets were prepared containing three subgroups each to test five different inducers. Microsomes were isolated by calcium precipitation. The levels of electron transport components, CYP 450, cytochrome b5, and cytochrome c-reductase were determined using extinction coefficients. Activities of drug-metabolizing enzymes were assayed. RESULTS: All inducers (phenobarbital, isoniazid, benzo(a)pyrene, clotrimazole, and clofibrate) showed significant induction of mixed function oxidase in chicken. The SDMP treatment of inducer-pretreated chicken caused a significant decrease in electron transport components and activities of drug-metabolizing enzymes when compared with treatment of inducer alone. Phenobarbital, isoniazid, and benzo(a)pyrene treatments of SDMP-pretreated chicken showed no significant change in induction pattern, however, significant alterations were observed in the induction pattern of clotrimazole and clofibrate. CONCLUSION : Our studies suggest that CYP 2B1, 2B2, 3A; CYP 2E1; CYP 1A1; CYP 3A and CYP 4A are susceptible species of CYP 450 to SDMP and its metabolites. The SDMP also affected in the induction pattern of some of the inducers with respect to CYP 450 isoforms