Methylazoxymethanol acetate

Last updated
Methylazoxymethanol acetate
Methylazoxymethanol acetate Formula V1.svg
Methylazoxymethanol Acetate 3D.png
Names
IUPAC name
(Z)-acetyloxymethylimino-methyl-oxidoazanium[ citation needed ]
Preferred IUPAC name
[(Z)-methyl-ONN-azoxy]methyl acetate
Other names
MAM
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.008.879 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 209-765-7
KEGG
MeSH D008746
PubChem CID
UNII
  • InChI=1S/C4H8N2O3/c1-4(7)9-3-5-6(2)8/h3H2,1-2H3/b6-5-
    Key: BELPJCDYWUCHKF-WAYWQWQTSA-N
  • InChI=1/C4H8N2O3/c1-4(7)9-3-5-6(2)8/h3H2,1-2H3/b6-5-
    Key: BELPJCDYWUCHKF-WAYWQWQTBQ
  • CC(=O)OC/N=[N+](/C)\[O-]
Properties
C4H8N2O3
Molar mass 132.11792
Hazards
GHS labelling:
GHS-pictogram-silhouette.svg
Danger
H350, H360D
P201, P202, P281, P308+P313, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Methylazoxymethanol acetate, MAM, is a neurotoxin which reduces DNA synthesis [1] used in making animal models of neurological diseases including schizophrenia [2] and epilepsy. [3] MAM is found in cycad seeds, and causes zamia staggers. It selectively targets neuroblasts in the central nervous system. In rats, administration of MAM affects structures in the brain which are developing most quickly. [2] It is an acetate of methylazoxymethanol.

Contents

MAM animal models

Schizophrenia

In rat models, the specific effect of MAM on neural development depends on the gestational age of the subject. At the seventeenth gestational day (GD17), administration of MAM produces behavioral and histopathological patterns found in schizophrenia. [2] The molecular mechanism behind this model is not fully known. [4] Methylazoxymethanol acetate administered at GD17 reduces the thickness of the hippocampus and the thalamus. The locomotor effects of amphetamines and the spontaneous firing rate of dopaminergic neurons in the ventral tegmental area are increased. In alternating maze tests, GD17 MAM rats quickly learned the first rule, but took longer to accommodate to alterations to the rule; this is thought to indicate deficits in working spatial memory, which is also impaired in schizophrenia. [2] Another study found that mice whom methylazoxy-methanol acetate was administered on 16th gestational day, but not those whom it was adminitred on GD17 showed decreased parvalbumin expression in hippocampus and prefrontal cortex, and schizophrenia-like characteristics. Mice whom MAM was administered on GD16 also exhibited reduced size of hippocampus and thinning of the prefrontal cortex. PFC-dependent cognitive deficits were shown only in male MAM-treated mice. [5]

Epilepsy

Exposure to MAM before birth increases susceptibility to epileptic seizures caused by flurothyl. [3] Prenatal MAM exposure in rats results in a model of brain malformation. In some MAM animals, video-EEG monitoring has documented the presence of spontaneous electrographic seizure activity [6] In some epilepsy rat models, MAM is administered at the fifteenth gestational day. Previous studies have found impaired cognitive function in GD15 MAM rats, and a reduced seizure threshold. [7] At the cellular level, dysplastic hippocampal neurons in the MAM model were shown to have reduced potassium current function and expression for the Kv4.2 channel subunit [8] These findings may contribute to the spontaneous seizures and reduced seizure thresholds seen in this model.

Related Research Articles

<span class="mw-page-title-main">Hippocampus</span> Vertebrate brain region involved in memory consolidation

The hippocampus is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, and plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. The hippocampus is located in the allocortex, with neural projections into the neocortex in humans, as well as primates. The hippocampus, as the medial pallium, is a structure found in all vertebrates. In humans, it contains two main interlocking parts: the hippocampus proper, and the dentate gyrus.

<span class="mw-page-title-main">Reelin</span> Large secreted extracellular matrix glycoprotein involved in neuronal migration

Reelin, encoded by the RELN gene, is a large secreted extracellular matrix glycoprotein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates synaptic plasticity by enhancing the induction and maintenance of long-term potentiation. It also stimulates dendrite and dendritic spine development and regulates the continuing migration of neuroblasts generated in adult neurogenesis sites like the subventricular and subgranular zones. It is found not only in the brain but also in the liver, thyroid gland, adrenal gland, Fallopian tube, breast and in comparatively lower levels across a range of anatomical regions.

<span class="mw-page-title-main">Focal cortical dysplasia</span> Medical condition

Focal cortical dysplasia (FCD) is a congenital abnormality of brain development where the neurons in an area of the brain failed to migrate in the proper formation in utero. Focal means that it is limited to a focal zone in any lobe. Focal cortical dysplasia is a common cause of intractable epilepsy in children and is a frequent cause of epilepsy in adults. There are three types of FCD with subtypes, including type 1a, 1b, 1c, 2a, 2b, 3a, 3b, 3c, and 3d, each with distinct histopathological features. All forms of focal cortical dysplasia lead to disorganization of the normal structure of the cerebral cortex :

An apical dendrite is a dendrite that emerges from the apex of a pyramidal cell. Apical dendrites are one of two primary categories of dendrites, and they distinguish the pyramidal cells from spiny stellate cells in the cortices. Pyramidal cells are found in the prefrontal cortex, the hippocampus, the entorhinal cortex, the olfactory cortex, and other areas. Dendrite arbors formed by apical dendrites are the means by which synaptic inputs into a cell are integrated. The apical dendrites in these regions contribute significantly to memory, learning, and sensory associations by modulating the excitatory and inhibitory signals received by the pyramidal cells.

<span class="mw-page-title-main">Subiculum</span> Most inferior part of the hippocampal formation

The subiculum is the most inferior component of the hippocampal formation. It lies between the entorhinal cortex and the CA1 subfield of the hippocampus proper.

<span class="mw-page-title-main">Hippocampal sclerosis</span> Medical condition

Hippocampal sclerosis (HS) or mesial temporal sclerosis (MTS) is a neuropathological condition with severe neuronal cell loss and gliosis in the hippocampus. Neuroimaging tests such as magnetic resonance imaging (MRI) and positron emission tomography (PET) may identify individuals with hippocampal sclerosis. Hippocampal sclerosis occurs in 3 distinct settings: mesial temporal lobe epilepsy, adult neurodegenerative disease and acute brain injury.

<span class="mw-page-title-main">Ventromedial nucleus of the hypothalamus</span> Nucleus of the hypothalamus

The ventromedial nucleus of the hypothalamus is a nucleus of the hypothalamus. In 2007, Kurrasch et al. found that the ventromedial hypothalamus is a distinct morphological nucleus involved in terminating hunger, fear, thermoregulation, and sexual activity. This nuclear region is involved in the recognition of the feeling of fullness.

Theta waves generate the theta rhythm, a neural oscillation in the brain that underlies various aspects of cognition and behavior, including learning, memory, and spatial navigation in many animals. It can be recorded using various electrophysiological methods, such as electroencephalogram (EEG), recorded either from inside the brain or from electrodes attached to the scalp.

<span class="mw-page-title-main">Temporal lobe epilepsy</span> Chronic focal seizure disorder

In the field of neurology, temporal lobe epilepsy is an enduring brain disorder that causes unprovoked seizures from the temporal lobe. Temporal lobe epilepsy is the most common type of focal onset epilepsy among adults. Seizure symptoms and behavior distinguish seizures arising from the medial temporal lobe from seizures arising from the lateral (neocortical) temporal lobe. Memory and psychiatric comorbidities may occur. Diagnosis relies on electroencephalographic (EEG) and neuroimaging studies. Anticonvulsant medications, epilepsy surgery and dietary treatments may improve seizure control.

Pachygyria is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, the onset and severity depending on the severity of the cortical malformation. Infantile spasms are common in affected children, as is intractable epilepsy.

<span class="mw-page-title-main">Perforant path</span>

In the brain, the perforant path or perforant pathway provides a connectional route from the entorhinal cortex to all fields of the hippocampal formation, including the dentate gyrus, all CA fields, and the subiculum.

<span class="mw-page-title-main">Seletracetam</span> Chemical compound

Seletracetam is a pyrrolidone-derived drug of the racetam family that is structurally related to levetiracetam. It was under development by UCB Pharmaceuticals as a more potent and effective anticonvulsant drug to replace levetiracetam but its development has been halted.

<span class="mw-page-title-main">Lacosamide</span> Anticonvulsant and analgesic medication

Lacosamide, sold under the brand name Vimpat among others, is a medication used for the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. It is used by mouth or intravenously.

<span class="mw-page-title-main">Spike-and-wave</span>

Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘petit mal’ epilepsy. The basic mechanisms underlying these patterns are complex and involve part of the cerebral cortex, the thalamocortical network, and intrinsic neuronal mechanisms.

Kindling is a commonly used model for the development of seizures and epilepsy in which the duration and behavioral involvement of induced seizures increases after seizures are induced repeatedly. Kindling is also referred as an animal visual model of epilepsy that can be produced by focal electrical stimulation in the brain. This is mainly used in visualising epilepsy in humans. The kindling model was first proposed in the late 1960s by Graham V. Goddard and colleagues. Although kindling is a widely used model, its applicability to human epilepsy is controversial.

<span class="mw-page-title-main">Environmental enrichment</span> Brain stimulation through physical and social surroundings

Environmental enrichment is the stimulation of the brain by its physical and social surroundings. Brains in richer, more stimulating environments have higher rates of synaptogenesis and more complex dendrite arbors, leading to increased brain activity. This effect takes place primarily during neurodevelopment, but also during adulthood to a lesser degree. With extra synapses there is also increased synapse activity, leading to an increased size and number of glial energy-support cells. Environmental enrichment also enhances capillary vasculation, providing the neurons and glial cells with extra energy. The neuropil expands, thickening the cortex. Research on rodent brains suggests that environmental enrichment may also lead to an increased rate of neurogenesis.

<span class="mw-page-title-main">Animal model of schizophrenia</span>

Research into the mental disorder of schizophrenia, involves multiple animal models as a tool, including in the preclinical stage of drug development.

Sharp waves and ripples (SWRs) are oscillatory patterns produced by extremely synchronised activity of neurons in the mammalian hippocampus and neighbouring regions which occur spontaneously in idle waking states or during NREM sleep. They can be observed with a variety of imaging methods, such as EEG. They are composed of large amplitude sharp waves in local field potential and produced by tens of thousands of neurons firing together within 30–100 ms window. They are some of the most synchronous oscillations patterns in the brain, making them susceptible to pathological patterns such as epilepsy.They have been extensively characterised and described by György Buzsáki and have been shown to be involved in memory consolidation in NREM sleep and the replay of memories acquired during wakefulness.

Cajal–Retzius cells are a heterogeneous population of morphologically and molecularly distinct reelin-producing cell types in the marginal zone/layer I of the developmental cerebral cortex and in the immature hippocampus of different species and at different times during embryogenesis and postnatal life.

<span class="mw-page-title-main">High-frequency oscillations</span> Brainwaves with frequencies larger than 80 Hz

High-frequency oscillations (HFO) are brain waves of the frequency faster than ~80 Hz, generated by neuronal cell population. High-frequency oscillations can be recorded during an electroencephalagram (EEG), local field potential (LFP) or electrocorticogram (ECoG) electrophysiology recordings. They are present in physiological state during sharp waves and ripples - oscillatory patterns involved in memory consolidation processes. HFOs are associated with pathophysiology of the brain like epileptic seizure and are often recorded during seizure onset. It makes a promising biomarker for the identification of the epileptogenic zone. Other studies points to the HFO role in psychiatric disorders and possible implications to psychotic episodes in schizophrenia.

References

  1. "Methylazoxymethanol Acetate – Compound Summary". PubChem . National Center for Biotechnology Information . Retrieved 9 June 2012.
  2. 1 2 3 4 Jones, CA; Watson, DJG; Fone, KCF (1 October 2011). "Animal models of schizophrenia". British Journal of Pharmacology . 164 (4): 1162–1194. doi:10.1111/j.1476-5381.2011.01386.x. PMC   3229756 . PMID   21449915.
  3. 1 2 Baraban, Scott C.; Schwartzkroin, Philip A. (31 March 1996). "Flurothyl seizure susceptibility in rats following prenatal methylazoxymethanol treatment". Epilepsy Research. 23 (3): 189–194. doi:10.1016/0920-1211(95)00094-1. PMID   8739122. S2CID   21818415.
  4. Hradetzky, Eva; et al. (28 September 2011). "The Methylazoxymethanol Acetate (MAM-E17) Rat Model: Molecular and Functional Effects in the Hippocampus". Neuropsychopharmacology. 37 (2): 364–377. doi:10.1038/npp.2011.219. PMC   3242314 . PMID   21956444.
  5. Chalkiadaki, Kleanthi; Velli, Aggeliki; Kyriazidis, Evangelos; Stavroulaki, Vasiliky; Vouvoutsis, Vasilis; Chatzaki, Ekaterini; Aivaliotis, Michalis; Sidiropoulou, Kyriaki. "Development of the MAM model of schizophrenia in mice: Sex similarities and differences of prefrontal cortical and hippocampal function" (PDF). bioRxiv.
  6. Harrington, Emily; et al. (January 2007). "Altered glutamate receptor-transporter and spontaneous seizures in rats exposed to methylazoxymethanol in utero". Epilepsia. 48 (1): 158–168. doi: 10.1111/j.1528-1167.2006.00838.x . PMID   17241223. S2CID   23267780.
  7. Moshé, editors, Asla Pitkänen, Philip A. Schwartzkroin, Solomon L. (2006). Models of seizures and epilepsy. Amsterdam: Elsevier Academic. pp. 305–312. ISBN   0120885549.{{cite book}}: |first= has generic name (help)
  8. Castro, Peter; et al. (1 September 2001). "AHippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy". Journal of Neuroscience. 21 (17): 6626–6634. doi:10.1111/j.1528-1167.2011.03264.x. PMC   3230777 . PMID   21933177.