Disease relevance of HSDB 3509

• S.c. administration of DMH, AOM, or MAM at dosages ranging from 0.2 to 0.8 mmol/kg of body weight caused dose-dependent increases in mutations of S. typhimurium in the host-mediated assay, and molar potencies increased progressively from DMH to AOM to MAM [1].
• However, the specific molecular targets that play a key role in MAM-induced brain injury remain unclear [2].
• 2. MAM reduces DNA repair in human and rodent neurons, whereas DNA-repair inhibitors potentiate MAM-induced DNA damage and toxicity in mature rodent nervous tissue [3].
• 3. Human neurons (SY5Y neuroblastoma) that are deficient in DNA repair are susceptible to MAM-induced cytotoxicity and DNA damage, whereas overexpression of DNA repair in similar cells is protective [3].
• MAM rats are therefore an interesting animal model of chronic brain damage induced transplacentally, which could serve for studying adaptive mechanisms of the CNS to this damage and its pharmacological manipulation [4].

Psychiatry related information on HSDB 3509

• Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia [5].
• In the rat, intraperitoneal injection of the anti-mitotic agent methylazoxymethanol (MAM) during intra-uterine development (embryonic day 17) induces cytoarchitectural abnormalities in the hippocampus and the cortex and behavioural changes reminiscent of positive, negative and cognitive symptoms of schizophrenia [6].

High impact information on HSDB 3509

• The cerebellar cortex continued to mature after exposure to MAM, but development of morphological endpoints examined here were static from PND19 to 33 [7].
• Methylazoxymethanol (MAM), another metabolite of DMH, was mutagenic in vitro without activation [1].
• Greater expiration of azomethane and decreased conversion of AOM to MAM, both seen with restriction of dietary protein, were associated with a smaller body burden of DMH metabolites [1].
• The capacity to encode periodic sensory stimuli is disrupted in MAM-treated somatosensory cortex; after an initial response to the onset of periodic stimuli, neurons in all cortical layers show weak entrainment [8].
• The interrupted laminar pattern that arises after early MAM injections coincides with distorted radial glial cells (identified by immunoreactivity to the intermediate filament protein, vimentin), which occur after early, but not late, MAM injections [9].

Biological context of HSDB 3509

• Our studies demonstrate that if early development of the neocortex is interrupted by injection of MAM during embryogenesis (on embryonic day 24 or 28; E24 or E28), a distinct laminar pattern fails to form properly in the parietal cortex [9].
• Our data demonstrated a clear reduction of p286-active form of alphaCaMKII and a selective impairment of both the targeting and the CaMKII-dependent phosphorylation of NR2A/B subunits in the postsynaptic membranes of the MAM-induced heterotopia [10].
• To reveal potential molecular networks targeted by MAM in the developing nervous system, we examined characteristic phenotypic changes (DNA damage, cytoarchitecture) induced by MAM and their correlation with gene expression differences using microarray assays (27,648 genes) [2].
• We propose that prenatal or postnatal exposure to low levels of cycasin/MAM may damage neuronal DNA, compromise DNA repair, perturb neuronal gene expression, and irreversibly alter cell function to precipitate a slowly evolving disease ("slow-toxin" hypothesis) [3].
• Analyses of the response to DMH and MAM by F1 reciprocal hybrids of the AKR and SWR strains have shown a complex inheritance pattern governing susceptibility to DMH [11].

Anatomical context of HSDB 3509

• Three day-old postnatal C57BL/6 mice (PND3) received a single injection of MAM and the cerebellum and cerebral cortex of PND4, 8, 15, and 22 mice were analyzed [2].
• These results suggest that MAM treatment induces long-lasting ablation of cortical NGF-synthesizing cells leading to reduced trophic support to basal forebrain cholinergic neurons, which might be responsible for the cellular atrophy observed in the basal nucleus [12].
• At higher MAM/MAMOAc concentrations (1.0 mM), widespread islet cell destruction was observed [13].
• DNA from postmitotic rodent central nervous system neurons is particularly sensitive to damage by MAM [3].
• In rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (NBM) or prenatally exposed to methylazoxymethanol (MAM), SL65.0155 (1 mg/kg/day, i.p.) administered for 7 days, improved the learning and memory capacity in animals tested in shuttle-box active avoidance and radial maze tests [14].

Associations of HSDB 3509 with other chemical compounds

• Methylazoxymethanol (MAM) is widely used as a developmental neurotoxin and exposure to its glucoside (i.e., cycasin) is associated with the prototypical neurological disorder western Pacific ALS/PDC [2].
• The number of reelin-positive neurons was increased whereas the total neuron number was decreased in the stratum oriens in the E17 MAM-exposed animals as compared to the control group [6].

Gene context of HSDB 3509

• Here we analyzed the NMDA receptor complex and associated proteins in the heterotopic neurons of 2- to 3-month-old MAM-treated rats by means of a combined immunocytochemical/molecular approach [10].
• NMDA-NR1 and AMPA-GluR2/3 subunits, as well as PSD-95 and total alphaCaMKII protein levels, were not affected in MAM-treated rats, thus revealing that the overall composition of the postsynaptic fraction was not altered [10].
• Total cortical ChAT activity of MAM 2, 19 and 27 month old animals was reduced compared to their age-matched controls [12].
• Not only an increase in the number of cells expressing reelin was observed, but there was also a slight increase in reelin mRNA levels in hippocampal pyramidal cells of MAM-exposed animals [6].

Analytical, diagnostic and therapeutic context of HSDB 3509

• Double intraperitoneal injections of methylazoxymethanol (MAM) in pregnant rats induce developmental brain dysgenesis with nodular heterotopia similar to human periventricular nodular heterotopia (PNH) and composed of hyperexcitable neurons [10].
• Studies are underway using DNA-repair proficient and deficient neuronal cell cultures and mutant mice to explore gene-environment interplay with respect to MAM treatment, DNA damage, and DNA repair, and the age-related appearance of neurobehavioral and neuropathological compromise [3].
• Pieces of donor cerebral cortex were transplanted to the cerebral hemispheres of normal newborn hosts at one day, two days, or 6 days after MAM treatment; survival was assessed 1-12 weeks after transplantation by autoradiography of histological sections [15].
• Consistently, dentate granule cell death, assessed by the TUNEL method, was significantly decreased in the MAM rats [16].

References