Regional distribution of cytochrome P450 2D1 in the rat central nervous system
4-hydroxylation; catecholamine metabolism; debrisoquine sparteine-type; dopamine; drug-metabolism; h-3 gbr-12935 binding; human-brain; immunohistochemical localization; multiple forms; Neurosciences & Neurology; neurotoxin; parkinsons-disease; parkinsons-disease; polymorphism; striatal membranes; transporter; xenobiotics; Zoology
Cytochrome P450s are enzymes involved in the oxidative metabolism of numerous endogenous and exogenous molecules. The enzyme cytochrome debrisoquine/sparteine-type monoxygenase is a specific form of cytochrome P450 and is found in the liver and the brain (in the rat the enzyme is known as CYP2D1). CYP2D1 has no established role in the brain; however, it has been shown to share substrate and inhibitor specificities with the dopamine transporter and the enzyme monoamine oxygenase B. Using CYP2D-specific deoxyoligonucleotide probes and a polyclonal antibody to CYP2D1, we have mapped the distribution of CYP2D mRNA and CYP2D1-like immunoreactivity in the rat central nervous system. CYP2D1 immunoreactivity and the CYP2D mRNA signal were heterogenously distributed between brain areas. There were moderate to high levels of immunoreactivity and mRNA signal in the olfactory bulb, olfactory tubercle, cerebral cortex, hippocampus, dentate gyrus, piriform cortex, caudate putamen, supraoptic nucleus, medial habenula, hypothalamus, thalamus, medial mamilliary nucleus and superior colliculus. In the brainstem, strong CYP2D1 immuno-reactivity and CYP2D mRNA signal were observed in the substantia nigra compacta, red nucleus, interpeduncular nucleus, pontine grey, locus coeruleus, cerebellum, and the ventral horn of the spinal cord. This study indicates that CYP2D1 is widely and constitutively expressed in neuronal and some glial populations in the rat brain. The localization of CYP2D1 in several regions known to harbor catecholamines and serotonin may suggest a role for CYP2D1 in the metabolism of monoamines. (C) 1996 Wiley-Liss, Inc.
Norris P J; Hardwick J P; Emson P C
Journal of Comparative Neurology
1996
1996-03
Journal Article
<a href="http://doi.org/10.1002/(sici)1096-9861(19960304)366:2%3C244::aid-cne5%3E3.3.co;2-i" target="_blank" rel="noreferrer noopener">10.1002/(sici)1096-9861(19960304)366:2%3C244::aid-cne5%3E3.3.co;2-i</a>
Dual-Target-Directed Drugs that Block Monoamine Oxidase B and Adenosine A(2A) Receptors for Parkinson's Disease
adenosine A(2A) receptor; antagonist; caffeine; dopaminergic neurotoxicity; dual-target-directed drug; human-brain; inhibition; istradefylline; l-dopa; mao-b; monoamine-oxidase-b; motor complications; Neurosciences & Neurology; parkinsons-disease; Pharmacology & Pharmacy; rat model; substantia-nigra
Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A(2A) receptor is one such target. Antagonists of this receptor (A(2A) antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A(2A) antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A(2A) antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A(2A) receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.
Petzer J P; Castagnoli N; Schwarzschild M A; Chen J F; Van der Schyf C J
Neurotherapeutics
2009
2009-01
Journal Article
<a href="http://doi.org/10.1016/j.nurt.2008.10.035" target="_blank" rel="noreferrer noopener">10.1016/j.nurt.2008.10.035</a>
Is humanlike cytoarchitectural asymmetry present in another species with complex social vocalization? A stereologic analysis of mustached bat auditory cortex
asymmetry; cerebral-cortex; combination-sensitive neurons; DSCF; hemispheric-specialization; human-brain; japanese macaques; lateralization; mustached bat; neural; Neurosciences & Neurology; planum temporale; pteronotus-parnellii; rhesus-monkeys; social vocalization; stereology; temporal speech region; V1
Considerable evidence suggests that left hemispheric lateralization for language comprehension in humans is associated with cortical microstructural asymmetries. However, despite the fact that left hemispheric dominance for the analysis of species-specific social vocalizations has been reported in several other species, little is known concerning microstructural asymmetries in auditory cortex of nonhumans. To test whether such neuroanatomical lateralization characterizes another species with complex social vocalizations, we performed stereologic analyses of Nissl-stained cells in layer III of area DSCF in mustached bats (Pteronotus parnellii). Area DSCF was selected because it contains neurons which are sensitive to several temporal features of conspecific vocalizations. Primary visual cortex (V I) was also studied as a comparative reference. We measured neuron densities, glial densities, and neuronal volumes in both hemispheres of 10 adult male bats. Results indicate that these variables are not significantly lateralized in area DSCF or V I. Additionally, magnopyramidal cells (i.e., the largest 10% of neurons from both hemispheres) were not asymmetric in their frequency of distribution at the population level. Although several individual bats had asymmetric neuron distributions, consistent hemispheric bias was not evident. Absence of population-level microstructural asymmetry in area DSCF of mustached bats suggests alternative evolutionary scenarios including: (1) microstructural lateralization of auditory cortical circuitry may be a unique adaptation for human language, and (2) the specialized biosonar function of mustached bat auditory cortex may require symmetrical cytoarchitectural structure. Resolution of these alternatives will require further data on the microstructure of auditory cortex in species with lateralized perception of acoustic social communication. (C) 2005 Elsevier B.V. All rights reserved.
Sherwood C C; Raghanti M A; Wenstrup J J
Brain Research
2005
2005-05
Journal Article
<a href="http://doi.org/10.1016/j.brainres.2005.03.023" target="_blank" rel="noreferrer noopener">10.1016/j.brainres.2005.03.023</a>