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By and tion that gives rise to the indirect pathway expresses prefer- large 40mg triamcinolone amex, projections from these areas target the same nuclei entially enkephalin and dopamine D2 receptors (105 purchase 15mg triamcinolone visa,176, that also receive GPi output, but tend to terminate in differ- 283), and may be the principal target of cortical inputs ent regions of these nuclei. Neurons in the lateral SNr compacta, on striatal output. Dopamine appears to modu- project preferentially to the lateral posterior region of VAmc late the activity of the basal ganglia output neurons in GPi and to different parts of the MD. These areas of the thala- and SNr by facilitation of transmission over the direct path- mus are predominately related to posterior regions of the way and inhibition of transmission over the indirect pathway frontal lobe including the frontal eye field and areas of the (104). The net effect of striatal dopamine release appears premotor cortex, respectively (140). As is the case with GPi, to be to reduce basal ganglia output to the thalamus and SNr also sends projections to the noncholinergic neurons other targets (see below). This implies that a reduction of in the medial two-thirds of the PPN (117,243,271,277). The latter projection is far more prominent in Basal ganglia output arises from both GPi and SNr. The phylogenetically old animal species (amphibians) than in segregation of GPi into a caudoventral 'motor' portion and primates (189). The motor territory of GPi projects almost exclusively to the posterior ROLE OF THE BASAL part of the ventrolateral nucleus (VLo in macaques), which GANGLIA–THALAMOCORTICAL CIRCUITRY in turn sends projections toward the supplementary motor IN THE CONTROL OF MOVEMENT area (SMA) (143,249,280), the primary motor cortex (MI) (135,136,143,148,152,213,241), and premotor (PM) cor- At the most basic level, voluntary movements appear to be tical areas (135). The outflow from pallidal motor areas initiated at the cortical level of the motor circuit with output directed at cortical areas MI, PM, and SMA appears to arise to brainstem and spinal cord, and to multiple subcortical from separate populations of pallidothalamic neurons (135), targets, including the thalamus, putamen, and the STN. The focusing model, however, is difficult to rec- logic properties of corticostriatal projection neurons have oncile with the fact that basal ganglia neurons become active shown that these neurons are different from corticospinal after changes in cortex and thalamus are manifest (13,63, projection neurons (20,295) and tend to have slower con- 73,75,103,202,293,294,309). Both models are at odds with duction velocities and lower spontaneous rates, and are usu- the fact that although STN lesions (thus an interference ally not responding to somatosensory input. A multitude targeted neurons with subsequent disinhibition of related of other motor functions of the basal ganglia are strong thalamocortical neurons (142). The net effect is increased candidates, such as a role in self-initiated (internally gener- activity in appropriate cortical neurons, resulting in a facili- ated) movements, in motor (procedural) learning, and in tation of the movement. In contrast, activation of the striatal movement sequencing (115,250,318). These can only be neurons that give rise to the indirect pathway will lead to mentioned in passing here, but will probably gain greater increased basal ganglia output and, presumably, to suppres- prominence in future models of basal ganglia function. Because the majority of neurons in GPi increase their firing rate with movement (103,202), the pre- sumed increased suppression of unintended competing CHANGES IN BASAL GANGLIA CIRCUIT movements may be a particularly important role of the basal ACTIVITY IN PARKINSONISM ganglia. Depending on the precise timing and anatomic connectivity, this dual action on movement could result in Regardless of the precise causation of the disease, all of the limiting the spatial or temporal extent of movements. The combina- that result from loss of dopaminergic transmission in the tion of information traveling via the direct and the indirect basal ganglia has been greatly facilitated by the discovery pathways of the motor circuit has been proposed to serve that primates treated with MPTP develop behavioral and to either scale or focus movements (7,200,211). Scaling anatomic changes that closely mimic the features of PD in would be achieved by a temporal sequence of activity humans (17,47,100,170). Striatal output would first in- Changes in the activity over striatopallidal pathways were hibit specific neuronal populations in GPi/SNr via the di- first suggested by studies in MPTP-induced parkinsonism rect pathway, thus facilitating movement, followed by disin- in primates that indicated that the metabolic activity (as hibition of the same GPi/SNr neuron via inputs over the measured with the 2-deoxyglucose technique) is increased indirect pathway, leading to inhibition ('braking') of the in both pallidal segments (60,201,222,252). In the focusing model, by contrast, inhi- preted as evidence of increased activity of the striatum-GPe bition of relevant pallidal/nigral neurons via the direct path- connection and the STN-GPi pathway, or, alternatively, as way would allow intended movements to proceed, whereas evidence of increased activity via the projections from the unintended movements would be suppressed by concomi- STN to both pallidal segments. It was then shown directly tant increased excitatory input via the indirect pathway in with microelectrode recordings of neuronal activity that other GPi/SNr neurons (see discussions in refs. Overall, the effect exerted by the two pathways in reduced tonic neuronal discharge in GPe, and increased this case would be to further shape or sculpt the movement. Raster displays of spontaneous neuronal activity recorded in different basal gan- glia structures within the basal ganglia circuitry in normal and parkinsonian primates. Shown are ten consecutive 1000-msec segments of data from the external and internal segments of the globus pallidus (GPe, GPi, respectively), the subthalamic nucleus (STN), and the substantia nigra pars reticulata (SNr). The neuronal activity is reduced in GPe, and increased in STN, GPi, and SNr. In addition to the rate changes, there are also obvious changes in the firing patterns of neurons in all four structures, with a marked prominence of burstiness and oscillatory discharge patterns in the parkinsonian state. In parkinsonian patients undergoing pallidotomy it has also been shown that the discharge rates in GPe are significantly lower than those in GPi (83,182,284,302), as had previously been shown in the MPTP-primate model. Recently, we have shown that treatment with MPTP results also in changes of neuronal activity in the second output nucleus of the basal ganglia, the SNr (Fig. These changes in activity are qualitatively similar to those occur- ring in GPi (312). In addition, loss of dopamine in the striatum should also lead to reduced activity via the inhibi- tory direct pathway. To date, this has not been directly demonstrated, however. The changes in discharge rates in the subnuclei of the basal ganglia have been interpreted as indicating that striatal dopamine depletion leads to increased activity of striatal neurons of the indirect pathway, resulting in inhibition of GPe, and subsequent disinhibition of STN and GPi/SNr.

Chen and co-workers found that coexpres- lowing KA treatment discount 4 mg triamcinolone free shipping, undergo necrosis when L-type volt- sion of huntingtin containing 138 repeats with NMDA re- age-dependent calcium channels are blocked (147) buy triamcinolone 10 mg line. Striatal spiny neurons are GLUTAMATE AND BRAIN DISORDERS selectively vulnerable in HD and ischemia, whereas large aspiny (LA) cholinergic interneurons of the striatum are Neurodegenerative Diseases spared in these pathologic conditions. Because NR1/NR2B HD is an autosomal dominant, progressive neurodegenera- is the predominant NMDA receptor expressed in medium tive disease that typically has its symptomatic onset in mid- spiny neostriatal neurons, this may contribute to the selec- life. Its manifestations include chorea, dementia, and death tive vulnerability of these neurons in HD (172). Afflicted individuals have an and associates found that membrane depolarization and in- expanded CAG repeat in the gene encoding huntingtin on ward currents produced by AMPA, KA, and NMDA were 80 Neuropsychopharmacology: The Fifth Generation of Progress much larger in spiny neurons than LA interneurons (173); ies have shown that ROS generated by A peptide inhibits moreover, concentrations of agonists producing reversible astrocyte glutamate uptake (181,182). The striatal and cortical neu- projection neurons in the hippocampus express iGluR sub- rons of R6/2 mice and mice with 94 CAG repeats displayed units from each receptor class; however, regional differences more rapid and increased swelling following NMDA treat- in immunoreactivity were apparent in AD versus normal ment than controls, whereas AMPA and KA treatments had brain. These findings suggest that NMDA GluR2(4), GluR5/6/7, and NR1 were reduced, presumably antagonists or compounds that alter sensitivity of NMDA owing to cell loss (183). In contrast, GluR2(4) immuno- receptors may be useful in the treatment of HD (174). The selective group I mGluR agonist autoradiography was also used to measure the laminar distri- 3,5-DHPG strongly enhanced membrane depolarization bution of NMDA and AMPA receptors in three areas of and intracellular calcium accumulation induced by NMDA visual cortex in control and AD postmortem human brains. Hyman and played decreased expression of AMPA- and KA- but not colleagues found no difference for the pattern of immuno- NMDA-type iGluR receptors compared to age-matched lit- staining between control and AD in either hippocampi or termate controls. These mice also had decreased expression adjacent temporal cortices for GluR1, GluR2/3, and GluR4 of mGluR1-3 that preceded the appearance of motor symp- (185); however, age-related loss of GluR2/3 immunoreac- toms; therefore, altered mGluR function may contribute to tivity prior to degeneration has been reported in nucleus subsequent pathology (176). Mac- receptors may leave these neurons vulnerable to degenera- Donald and associates examined a TAA repeat polymor- tion in AD. Western blot analysis revealed average reduc- phism, which is closely linked to the GluR6 gene, in 258 tions of approximately 40% for GluR1 and GluR2/3 in the unrelated HD-affected persons and found that younger entorhinal cortex of patients with AD pathology versus age- onset age of HD was associated with linkage disequilibrium matched controls, but neither GluR1 nor GluR2/3 protein for this polymorphism (177). Rubinsztein and co-workers concentration correlated significantly with tangle density found that 13% of the variance in the age of onset of HD (188). Thus, the relationship between excitotoxicity and that was not accounted for by the CAG repeat size could neuronal loss in AD is complex and requires additional in- be attributed to GluR6 genotype variation (178). Death results from compli- acterized by a cortical neurodegeneration, particularly in the cations of the progressive paralysis. The two forms of ALS, entorhinal cortex, hippocampal CA1 region, and subicu- sporadic and familial (FALS), have similar clinical symp- lum. The etiology of AD is complex, with age, trauma, toms and neuropathology, although the latter only accounts health, and environmental and genetic factors all playing a for 10% of the cases. Mutations Cu/Zn superoxide dismutase (SOD1), and identified 11 in the presenilin-1 (PS1) gene are causally linked to many different SOD1 missense mutations in 13 different FALS cases of early-onset inherited autosomal dominant AD. Expression of high levels of a mutant form Mice transgenic for the PS1M146V gene are hypersensitive of human SOD1 for which the glycine at position 93 was to seizure-induced synaptic degeneration and necrotic neu- replaced with an alanine (G93ASOD1; a change that has ronal death in the hippocampus (180). Cultured hippocam- little effect on enzyme activity) caused a progressive motor pal neurons from PS1M146V knock in mice display in- neuron disease resulting in death by 6 months in transgenic creased vulnerability to glutamate, which is correlated with mice (191). Because the mouse gene for SOD1 is unaffected perturbed calcium homeostasis, increased oxidative stress, in the transgenic mice, the results indicate that these muta- and mitochondrial dysfunction. Glutamate toxicity is po- tions in SOD1 cause a gain-of-function that results in motor tentiated by ROS mediated inhibition of EAATs; two stud- neuron death. Chapter 6: L-Glutamic Acid in Brain Signal Transduction 81 The reason for the selective vulnerability of motor neu- inotropic non–NMDA receptors may be of value in the rons in ALS is unknown. Various molecular and neuro- treatment of motor neuron disease (198). Further research chemical features of human motor neurons may render this may allow the development of therapies that target specific cell group differentially vulnerable to such insults. Motor neurons have a very high expression of the cytosolic free radical scavenging enzyme Cu/ZnSOD1, which may render SCHIZOPHRENIA this cell group more vulnerable to genetic or posttransla- tional alterations interfering with the function of this pro- Kim and associates reported diminished concentrations of tein. The low expression of calcium binding proteins and glutamate in CSF of patients with schizophrenia and first GluR2 AMPA receptor subunit by vulnerable motor neuron proposed that hypofunction of glutamatergic systems might groups may render them unduly susceptible to calcium- cause the disorder (199). This finding has been replicated mediated toxic events following GluR activation (192). In a High levels of mRNA for GluR1, GluR3, and GluR4 are postmortem study, Tsai and associates (140) studied eight expressed in normal human spinal motor neurons; however, brain regions and found decreased concentrations of gluta- GluR2 subunit mRNA was not detectable in this cell group, mate and aspartate in the frontal cortex and decreased con- predicting that normal human spinal motor neurons express centration of glutamate in the hippocampus of patients with calcium-permeable AMPA receptors unlike most neuronal schizophrenia as compared to controls. Furthermore, the groups in the human CNS (193); however, this has not been concentration of NAAG was increased in the hippocampus borne out in studies of mouse spinal cord in the context of and the activity of GCPII was selectively reduced in the the mouse models of ALS, where GluR2 is well represented frontal cortex, temporal cortex, and hippocampus of people in spinal cord motor neurons (194). Subsequent studies with magnetic reso- sure triggers substantial mitochondrial calcium loading in nance spectroscopy have revealed significant reductions in motor neurons, but causes little mitochondrial accumula- the level of N-acetylaspartate (NAA), the product of NAAG tion in forebrain GABAergic interneurons, neurons that ex- by GCPII, in the very same regions—frontal cortex, tem- press large numbers of calcium-permeable AMPA/kainate poral cortex, and hippocampus (204). Brief exposure to Initial ligand binding studies in postmortem schizo- either AMPA or kainate caused mitochondrial depolariza- phrenic brain have revealed increases in the non–NMDA tion in motor neurons, whereas these effects were only ob- iGLURs in the prefrontal cortex (205,206) and decreases served in the GABAergic neurons after exposure to the non- in the hippocampus (207,208).

Charney and Del- theories of depression generic 4mg triamcinolone with mastercard, DA has been emphasized far less in gado have pioneered in the use of an amino acid cocktail depression in spite of its being widely distributed in brain buy triamcinolone 4 mg. In these lite, are decreased in depressives (2,85,86), although some studies, the drink was first administered to subjects who had studies have reported elevated CSF DA, but not HVA levels responded to various antidepressants and who were being (87). Urinary DOPAC levels are decreased in depressives maintained on medication. Diphenhydramine has been compared with controls (88); in one study, DOPAC levels commonly used as the comparison cocktail. Euthymic pa- appeared associated with suicidal behavior (85). Dopami- tients on SSRIs but not TCAs rapidly experienced depres- nergic agents such as psychostimulants, nomifensine, and sive symptoms when depleted of L-tryptophan, suggesting the dopamine agonist pramipexole all have antidepressant the need for maintaining adequate serotonin levels to ensure effects in nondelusional patients. Parallel decreases in glu- In contrast, elevated mesolimbic DA activity has been cose utilization in frontal and thalamic regions using PET hypothesized to play a role in delusional depression (89). In contrast, there are multiple chotic symptoms and agitation in major depression (89), reports of depletion not causing a clear recurrence of symp- and increased plasma DA and HVA levels have also been toms in patients treated with bupropion or electroconvul- reported in delusional depression (90,91). Studies have used a variety of dif- limbic DA activity has been postulated to occur secondary ferent methods (e. Recent studies in rats, nonhuman primates, and differences may account for the discrepant findings. The psychotic depressives suggest elevated glucocorticoid activ- degree and duration of response observed before the deple- ity could also result in altered or decreased prefrontal corti- tion challenge is administered may be of particular impor- cal dopamine metabolism and to alterations in attention tance (79). Patients who are in remission or have shown a and response inhibition (92,93). These data suggest in- prolonged response are unlikely to demonstrate significant creased HPA axis activity could affect DA turnover differ- worsening of moods (79). These data suggest recent re- ently in specific brain regions—alterations that have been sponders are those who are susceptible to experiencing re- suggested in schizophrenia. Antipsychotic drugs appear to lapse with depletion strategies. Depletion of unmedicated play a key role in treatment of delusional depression and euthymic depressives does not appear to induce recurrence, glucocorticoid receptor antagonists are being actively stud- indicating maintaining serotonin tone is important primar- ied in the disorder. Of interest is a recent report that women controls show GABA much lower rates of 5HT synthesis and a greater decrease in response to depletion than men do (80). This gender- GABA has become a focus of greater study over the past based difference is consistent with a recent observation that several years with the increasing use of anticonvulsants in chronically depressed women are more responsive to an mood disorders. GABA is a major inhibitory neurotransmit- SSRIthan men are (81). There are two types of Fenfluramine Challenge GABA receptors. GABAA receptors have been studied in anxiolysis because of their location within a benzodiaze- Fenfluramine, previously marketed as an appetite suppres- pine–GABA receptor complex that is coupled to chloride sant, causes a release of serotonin from presynaptic neurons 2 channels. Prolactin responses In rats, antidepressants and mood stabilizers appear to up- to fenfluramine challenge are blunted in depressed patients regulate frontal-cortical GABAB, but not GABAA, receptors (82,83) and there are some data to suggest this may be a (94,95). GABAB agonists may enhance cAMP responses to trait marker (84). However, bipolar manic and axis II pa- norepinephrine and -adrenergic down-regulation in re- tients may also demonstrate blunted prolactin responses, sponse to tricyclic antidepressants, suggesting a facilitative raising questions regarding the specificity of the test. GABA levels have DOPAMINE been reported to be decreased in the CSF of depressed pa- tients in some but not all studies (96,97). Plasma GABA As indicated, dopamine (DA) is a precursor for norepineph- levels have also been reported to be lower in unipolar depres- rine. Although NE has played a central role in etiologic sives (98,99), and this may not normalize with treatment 1044 Neuropsychopharmacology: The Fifth Generation of Progress (100). Alcoholism can also be associated with low plasma drome contributor to DEX nonsuppression, greater than GABA levels (101). In refractory depressed patients the effect of severity or melancholia (107). Outpatients with undergoing cingulotomy, GABA levels are inversely related milder and nonpsychotic disorders show much lower rates to degree of depression (102). This difference in types of patients stud- tively exploring using fMRIto image GABA in the brains ied may help explain the variability in DEX nonsuppression of patients with mood disorders, both before and after treat- rates across studies. NEUROENDOCRINE SYSTEMS Glucocorticoid overactivity has been hypothesized to play a direct role in the development of cognitive impair- Neuroendocrine systems were originally studied as gateways ment and delusions in patients with psychotic major depres- to the exploration of neurotransmitter activity, such as nor- sion (89). Trials are currently underway exploring the effi- epinephrine and serotonin, in depression.

Hyperexcitability in combined entorhinal/hip- tive in vitro receptor autoradiography order triamcinolone 40mg otc. Neuroscience 1999;94: pocampal slices of adult rat after exposure to brain-derived neu- 1051–1061 generic 15 mg triamcinolone fast delivery. Effects of kainic acid on of the NMDAR1glutamate receptor subunit in human tem- messenger RNA levels of IL1IL6, TNF , and Lif in the rat poral lobe epilepsy. Increased neuronal - so dormant in temporal lobe epilepsy: a critical reappraisal of the amyloid precursor protein expression in human temporal lobe dormant basket cell hypothesis. Evidence of functional mossy fiber Neurochem 1994;63:1872–1879. Seizure activity causes elevation of en- cortex following aminoxyacetic acid-induced seizures. Exp Brain dogenous extracellular kynurenic acid in the rat brain. Rat 3-hydroxyanthranilic acid¨ ical changes of the cortical GABAergic system in epileptic foci. Chronic focal neocortical tivity and microglia are enhanced in the rat hippocampus by Chapter 127: Temporal Lobe Epilepsy 1855 focal kainate application: functional evidence for enhancement 97. Neuron loss, granule cell axon reor- of electrographic seizures. Loss of 2/NeuroD leads mental temporal lobe epilepsy. J Comp Neurol 1999;408: to malformation of the dentate gyrus and epilepsy. Hippocampal granule cells empress glu- of dentate gyrus neurons after single and intermittent limbic tamic acid decarboxylase-67 after limbic seizures in the rat. Expression of brain- of granule cell progenitors in the dentate gyrus of the adult rat. Cellular neurogenesis is increased by seizures and contributes to aberrant hybridization for BDNF, trkB, and NGF mRNAs and BDNF- network reorganization in the adult rat hippocampus. J Neurosci immunoreactivity in rat forebrain after pilocarpine induced sta- 1997;17:3727–3728. Seizure-induced changes in neurotrophin expression: hilar/CA3 border after status epilepticus and their synchrony implications for epilepsy. Brain-derived neuro- trophic factor (BDNF) transgenic mice exhibit passive avoid- seizure-induced neurogenesis. Neurogenesis in the ability in the hippocampus and entorhinal cortex. Axonal sprouting in layer parallels with the dentate gyrus. In: Scharfman HE, Witter MP, V pyramidal neurons of chronically injured cerebral cortex. The parahippocampal region: basic science and Neurosci 1995;12:8234–8245. The essential role of hippo- expression in the striatum in vivo. Neurosci Lett 1997;237: campal CA1NMDA receptor-dependent synaptic plasticity in 121–124. TAMMINGA Diseases of the brain include human motor disorders and understanding of PD is emerging; this presents a gauge for epilepsy, which are distinguished from primary behavioral the difficulty of the work and insight involved in under- disorders by the nature of their illness manifestations. Es- job of presenting the molecular anatomy and physiology of pecially the features of cerebral pathology and genetic associ- the basal ganglia thalamocortical network as it relates to ation make it easier to model the critical disease elements PD. It is this feature of network pathology, advanced for in the animal and to move more directly to the neural under- several decades by these investigators, that continues to in- pinnings of pathology in human brain. Identified cerebral form not only motor disorder research but aspects of cogni- pathology provides an opportunity for targeting the in- tion and affective research as well. Moreover, identification volved central nervous system (CNS) regions and known of the importance of the structures in this network in these brain networks for modeling and focused study. These kinds brain diseases has allowed many different investigators to of CNS illnesses not only serve as models for behavioral contribute data to produce a rich anatomic and electrophys- disorders of a successful experimental approach, but also iologic database of broad relevance for neural mechanisms. They weave together clinical experience and practical field to focus on a relevant region of the brain to explain clinical findings with the known neuropharmacology of the the neural substrate of Parkinsonian symptoms. L-dopa, dopamine agonists, anticholinergics, and The chapter by Zigmond and Burke addresses the clinical other drug treatments are critically reviewed in detail as are features and critical pathophysiology of PD, and illustrates the newer surgical and transplantation therapies now widely the value of critical genetic information in the understand- discussed. The broad knowledge base available for under- ing of PD, as well as clear descriptions of tissue pathology. After encountering the significant advances made whether free-radical–mediated injury, programmed cell in PD, discoveries in other CNS diseases appear more death, or effects of protein aggregation in tissue (or some modest. They describe the characteristic motor, cog- nitive, and psychiatric symptoms and the usual symptom- CarolA. Tamminga: UniversityofMaryland Schoolof Medicine;Deputy atic treatments. The known genetic etiology of HD Director, Maryland Psychiatric Research Center, Baltimore, Maryland.