Neurotransmitter Replacement Research Articles

Stimulation of the brain NO/cyclic GMP pathway by peripheral administration of tetrahydrobiopterin in the hph-1 mouse.

Mutations in GTP-cyclohydrolase I (GTP-CH) have been identified as causing a range of inborn errors of metabolism, including dopa-responsive dystonia. GTP-CH catalyses the first step in the biosynthesis of tetrahydrobiopterin (BH4), a cofactor necessary for the synthesis of catecholamines and serotonin. Current therapy based on monoamine neurotransmitter replacement may be only partially successful in correcting the neurological deficits. The reason might be that BH4 is also a cofactor for nitric oxide synthase. Using a strain of mutant GTP-CH-deficient (hph-1) mice, we demonstrate that in addition to impaired monoamine metabolism, BH4 deficiency is also associated with diminished nitric oxide synthesis in the brain (as evaluated by measuring the levels of cyclic GMP), when compared with wild-type animals. We have found a decline in the levels of BH4 with age in all animals, but no gender-related differences. We found a strong association between the levels of BH4 and cyclic GMP in hph-1 mice but not in wild-type animals. We also demonstrate that acute peripheral administration of BH4 (100 micromol/kg s.c.) in hph-1 mice significantly elevated the brain BH4 concentration and subsequently cyclic GMP levels in cerebellum, with peaks at 2 and 3 h, respectively. We suggest that BH4 administration should be considered in BH4 deficiency states in addition to monoamine replacement therapy.

MULTIPLE SYSTEM ATROPHY

MSA is a complex disorder, with regard to its pathology and cause as well as its clinical diagnosis and treatment. Although a number of clinical treatments may improve quality of life for these patients, given the widespread pathology present, symptomatic treatment, particularly that involving neurotransmitter replacement, is likely to remain difficult. Truly effective treatment for these patients is likely to depend on an understanding of the underlying pathogenic mechanisms and methods to halt or reverse disease progression. A firm understanding of the classification of these disorders is the first step to understanding the relevant pathogenic mechanisms. The finding of intracytoplasmic glial inclusion bodies provides a compelling piece of evidence that SND, OPCA, and SDS do, in fact, belong to one nosologic entity. These inclusions do not seem to be present in familial cases of OPCA; thus, they may provide a means to improve diagnostic specificity as well as sensitivity. With the ability to define clearly the entity of MSA, an understanding of the pathophysiology can be developed along with other degenerative neurologic diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease.

Pharmacological therapy in progressive supranuclear palsy.

To our knowledge, previous reports on drug treatment in progressive supranuclear palsy have not evaluated autopsy-confirmed cases. To evaluate pharmacological treatment responses from detailed clinical records in patients with autopsy-confirmed progressive supranuclear palsy. We reviewed medical records for clinical presentation and pharmacological response in 12 patients with autopsy-confirmed progressive supranuclear palsy diagnosed using the National Institute of Neurological Disorders and Stroke pathologic criteria. For each drug class, exposure, global positive response, and specific positive response (parkinsonism, other movement disorders, or gaze dysfunction) were recorded. Drug classes examined were dopaminergics (all patients), tricyclics (3 patients), methysergide maleate (3 patients), 5-hydroxytryptophan (2 patients), and anticholinergics and selective serotonin inhibitors (1 patient). Positive clinical response was detected in 7 of the patients receiving dopaminergic drugs and in 1 patient each receiving tricyclics, methysergide, and 5-hydroxytryptophan, respectively. None of the patients responded markedly however, and there was no persistent beneficial effect. Use of dopaminergic drugs most frequently improved parkinsonian features, but disabling adverse effects included orthostatic hypotension (6 patients), hallucinations and delusions (3 patients), gastrointestinal complaints (3 patients), and dizziness (1 patient). Only 1 patient developed dyskinesia. Use of antiparkinsonian medications and other neurotransmitter replacement therapies was largely ineffective and caused frequent adverse effects in this series of patients with autopsy-confirmed with progressive supranuclear palsy.

Unifying concepts in mechanism of amblyopia

Most of the evidence of formation of amblyopia is derived traditionally from electrophysiological studies. Recently, there have been many discoveries from genetics, histopathology, biochemistry, immunology and interventional studies. On the basis of evidence gathered in the last five years, the various types of amblyopia (strabismic and non-strabismic amblyopia) can be seen not only as disturbance of the development of the visual system at different points but as basically different pathologic processes. It is postulated here that strabismic amblyopia is initiated as a maladaptive differentiation in the ocular dominance columns, whereas the non-strabismic amblyopia may be initiated from the ganglion cell population of the amblyopic eye. The total clinical picture is confusing because of secondary changes in other parts of the central nervous system. The manifested features can be due to a slower, more enduring type of change (pooling, loss and re-wiring of the neurones) as well as a more transient, adaptive type of response (such as suppression of diplopia). Neurotransmitter replacement has a potential therapeutic application.

Neurotransmitter Receptor/G-protein Mediated Signal Transduction in Alzheimer's Disease Brain

Recent evidence suggests that the neurochemical pathology of Alzheimer's disease includes severe disruptions of the neurotransmitter receptor/G-protein mediated phosphatidylinositol hydrolysis and adenylyl cyclase signal transduction pathways. The present article briefly reviews evidence from postmortem studies describing disruptions to these systems and speculates as to the importance of these changes in terms of contributing to disease pathology and limiting the success of neurotransmitter replacement strategies.

Receptor-effector coupling dysfunctions in Alzheimer's disease.

There is now good evidence that in the AD brain, a number of neurotransmitter effector systems are defective. Such abnormalities include defective G, protein and protein kinase C function as well as a drastically reduced level of receptors for the second messenger Ins(1,4,5) P3. Such changes are probably not restricted to the late stages of the disease, and are found in regions of the brain that show little histopathological abnormality, such as the cerebellum. Whether these changes precede or are secondary to primary histopathological changes such as beta-amyloid deposition is not as yet clear. What is clear, however, is that such signal transduction abnormalities are likely to negate therapeutic benefits in clinical strategies based upon the tenet of neurotransmitter replacement.

Neurotransmitters, signal transduction and second-messengers in Alzheimer's disease.

It has long been assumed that widespread changes in postsynaptic neurotransmitter receptor function are not a feature of the disrupted neurotransmission seen in the brains with Alzheimer's disease (AD). However, recent evidence from postmortem brain and fibroblast studies suggests that both the neurotransmitter receptor/G-protein-modulated adenylyl cyclase and the phosphatidylinositol hydrolysis signal transduction cascades are disrupted in AD. Such disruptions may severely limit the functional integrity of key receptor types and undermine pharmacological attempts to ameliorate disease symptomatology through neurotransmitter replacement strategies. The involvement of some signalling mechanisms in the regulation of beta-amyloid precursor protein metabolism suggests also that disrupted signal transduction may exacerbate AD pathology.

Altered G-protein coupling of a frontal cortical low affinity [ 3H]8-hydroxy- N,N-dipropyl-2-aminotetralin serotonergic binding site in Alzheimer's disease

In Alzheimer's disease (AD), there are marked deficits in the function of both the cholinergic and serotonergic systems. We and others have shown altered muscarinic M1 receptor/G-protein coupling in the superior frontal cortex (Brodmann areas 8 and 9) from AD patients. In the present study, we investigated whether similar receptor/G-protein alterations would occur at the 5-HT 1 A receptor in the same brain area. Using [ 3H]8-OH-DPAT as a radioligand, two binding sites with high and low affinity were found. The high affinity site ( K d = 1 nM), which is consistent with the classical 5-HT 1 A receptor, was not affected in AD either in the absence or presence of the non-hydrolyzable guanine nucleotide analog, GppNHp (100 μM). On the other hand, although there was no change in the affinity of [ 3H]8-OH-DPAT at the low affinity site ( K d = 8–10 nM), agonist binding was less sensitive to inhibition by GppNHp in AD (−29%) compared to age-matched controls (−51%). Based on these findings, alterations in receptor/G-protein coupling of both cholinergic and serotonergic receptors may be one explanation why neurotransmitter replacement drug therapies have been unsuccessful thus far in the treatment of AD.

Parkinson's disease: past, present, and future.

The development of understanding of the pathophysiology and modes of treatment of Parkinson's disease represents one of the triumphs of modern medicine, encompassing astute clinical observation, utilization of basic research findings regarding dopamine to develop the first rational treatment of a degenerative disorder of the central nervous system, and remains at the frontiers of neurologic science. After characterization of the clinical and pathologic features of Parkinson's disease, rational treatment awaited the discovery of the deficit in basal ganglia dopamine. On the basis of this observation and the known biosynthetic pathways for dopamine formation, levodopa was introduced. Use of metabolic inhibitors to prolong and potentiate the effects and avoid the deleterious side effects of levodopa enhanced the efficacy of this neurotransmitter replacement strategy. The discovery and characterization of dopamine receptor subtypes and the availability of selective dopamine agonists provided additional therapeutic approaches, but failed to address the underlying cause of the degenerative process. The discovery and disclosure of the mechanisms of toxicity of the relatively selective nigrostriatal neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), triggered a resurgence of interest in etiological factors which might contribute to the development of parkinsonism and together with the report that inhibition of monoamine oxidase B with deprenyl not only potentiated the effects of levodopa, but appeared to prolong the life of parkinsonian patients, resulted in a large-scale trial of drugs that might arrest the degenerative process. Furthermore, the MPTP primate model of Parkinson's disease has encouraged development of fetal mesencephalic and other tissue implant approaches to reversal of parkinsonism. Although much of this is still in the experimental stages, hopes are high that new and more effective therapies will be developed and that similar techniques might be applicable to a wide variety of neuropsychiatric disorders.

Neurochemical Substrates of Human Aging and Dementia

Further development of clinical models of dementia to augment present unsatisfactory animal models, is of central importance to the understanding of the neurochemistry of dementia. Furthermore, present definitions of the neurotoxic processes underlying dementing disorders will need to be improved. Routine clinical markers will be necessary for the development of any therapy beyond present attempts for symptomatic treatment with neurotransmitter replacement.

Distribution of a somatostatin analog after continuous intraventricular administration.

Decreased somatostatin in the brains of patients with Alzheimer's disease has led to an investigation of the efficacy of neurotransmitter replacement therapy. The distribution of a somatostatin analog, octreotide, was determined after 2 to 6 days of continuous intraventricular infusion at 40 micrograms/h in dogs. The tissue concentration was greater than 100 ng/g wet weight in all parts of the brain, which is greater than the normal concentration of native somatostatin. There was no reduction in native somatostatin production because of the infusion of the analog. The cerebrospinal fluid octreotide concentration was 1000 times greater than the plasma concentration. The results demonstrate that neurotransmitter replacement for somatostatin can be achieved by chronic intraventricular infusion of a metabolically stable analog.

Distribution of a somatostatin analog after continuous intraventricular administration

Decreased somatostatin in the brains of patients with Alzheimer's disease has led to an investigation of the efficacy of neurotransmitter replacement therapy. The distribution of a somatostatin analog, octreotide, was determined after 2 to 6 days of continuous intraventricular infusion at 40 μg/h in dogs. The tissue concentration was greater than 100 ng/g wet weight in all parts of the brain, which is greater than the normal concentration of native somatostatin. There was no reduction in native somatostatin production because of the infusion of the analog. The cerebrospinal fluid octreotide concentration was 1000 times greater than the plasma concentration. The results demonstrate that neurotransmitter replacement for somatostatin can be achieved by chronic intraventricular infusion of a metabolically stable analog. (Neurosurgery 24:744-748, 1989)

New intrathecal drugs in Alzheimer's disease and psychometric testing.

Bethanechol chloride, a muscarinic agonist, was administered intrathecally to a sample of AD patients in double-blind crossover and open escalating-dose trials. There was a modest amelioration of disturbed behavior at a moderately high dose level, but no improvement in memory or cognition was seen at any dose. At the highest dose, cognition deteriorated. These findings, in conjunction with the results of the multicenter trial described by Harbaugh, suggest that the clinical efficacy of bethanechol in AD is limited. The disappointing results of trials with varied cholinomimetic therapies suggest that more than one biochemical abnormality is responsible for the AD dementia. The neuropeptide, somatostatin, is also reduced in AD, and the level of reduction is correlated with the degree of dementia. Manipulation of this transmitter, alone or in conjunction with acetylcholine, would appear to be a next logical step in the development of an effective neurotransmitter replacement therapy for AD. Implanted drug pumps will be needed for such clinical trials. The naturally occurring somatostatin-14 is not suitable because of its short half life. Sandostatin, an analog, is chemically stable and not metabolized by brain tissue. It does not cross the blood-brain barrier so that intrathecal administration is necessary. Pharmacological research in AD is complicated by a variety of psychometric problems including the criterion-related and construct validity of the outcome measures. Patients differ in their tolerance of various therapeutic agents and in the extent of the neurochemical pathology. It is critically important, therefore, to evaluate individual, as well as group, responses to treatment. The telephone log method may provide a useful way of generating enough observations for single subject analyses without overburdening the patient with repeated testing.

Tetrahydrobiopterin deficiencies: Preliminary analysis from an international survey

Tetrahydrobiopterin deficiency is a rare cause of hyperphenylalaninemic syndromes. The natural history of the disease is characterized by progressive neurologic illness unresponsive to a phenylalanine-restricted diet. Fifty patients have been reported. From the documented cases, the following statements can be made: (1) An incidence of 2% among hyperphenylalaninemic babies can be reasonably estimated. (2) Most patients have high neonatal blood phenylalanine concentrations, but some have only mild elevations. (3) Among the available diagnostic tests, measurement of urine pteridines should be proposed in all hyperphenylalaninemic babies, (4) The tolerance to dietary phenylalanine is generally high. (5) The results of neurotransmitter replacement therapy are encouraging, but treatment should be started within the first month and requires a strict follow-up protocol. Consequently, in every newborn infant with positive Guthrie test results, a rapid investigation of BH4 metabolism should be accomplished in order to differentiate between phenylalanine-hydroxylase deficiencies (phenylketonuria, mild hyperphenylalaninemia, transient hyperphenylalaninemia) and BH4 deficiencies.

Parkinson's disease and Alzheimer's disease as disorders of the isodendritic core.

Parkinson's disease and Alzheimer's disease may represent two parts of a spectrum of disease characterised by a primary loss of cells of the isodendritic core. Secondary cell loss from the striatum and cerebral cortex therefore occurs as a consequence of the loss of ascending projections from the isodendritic cells. The anatomy of this system should provide a unique opportunity for therapeutic intervention. Neurotransmitter replacement treatment may be provided either by enhancing transmitter release by any remaining neurones or by direct agonists. The wide dispersal of the isodendritic projection systems affected in Parkinson's and Alzheimer's disease and the possibility that they are tonically active create an opportunity for neurotransmitter replacement treatment. Animal studies should be able to show whether such treatment can delay secondary cell loss, and, together with human postmortem studies, whether the hypothesis that the primary lesion is a loss of isodendritic cells is correct.

Screening for Biopterin Disorders in PKU

It is now recognized (Pediatrics 65:806, 1980) that a small proportion of cases of phenylketonuria (PKU) may be due to abnormalities in the metabolism of biopterin. These cases do not respond to the restriction of dietary phenylalanine, but may be benefited by neurotransmitter replacement therapy. A specific diagnosis is therefore desirable. The Nutrition Committee of the American Academy of Pediatrics, in conjunction with the Society for Inherited Disease, announces the availability of an exploratory screening program for new cases of PKU for urinary biopterins.