Parkinson's disease: causes and pathogenesis

Causes of Parkinson's Disease

The development of parkinsonism can also be associated with exposure to certain toxins, such as manganese, carbon monoxide, and MTPF.

Manganese . Parkinsonian syndrome in experimental animals and miners can occur under the influence of a high concentration of manganese. The pathomorphological basis of manganese parkinsonism is the loss of the neurons of the pale sphere and the black substance, probably as a result of the direct toxic action of the metal.

Carbon monoxide (carbon monoxide). Parkinsonism can be caused by exposure to a high concentration of carbon monoxide. This variant of toxic parkinsonism usually does not react to levodopa preparations, which makes it possible to distinguish it from Parkinson's disease. At the heart of the syndrome lies the death of the striatum neurons and the pale sphere.

MPTP. Several drug addicts who injected intravenously intravenously meperidine with an admixture of MPTF developed Parkinsonian syndrome. Later it was reproduced in laboratory animals by the introduction of one MPTP. It is believed that MPTP is transformed by MAO type B into an active metabolite, MPF +, which accumulates in the dopaminergic endings with the help of a dopamine high affinity transport system. In dopaminergic neurons, MPF + is stored, being associated with neuromelanin. Slowly releasing, it inhibits the complex of the I mitochondria of the electron transport chain, contributing to the excessive formation of free radicals, toxic to neurons. Although MPF + is able to inhibit complex I in other cells, they are released faster than dopaminergic neurons.

PET in several asymptomatic individuals who injected MPTF, revealed a decrease in the number of dopaminergic endings. Several of these individuals subsequently developed Parkinson's symptoms. This again confirms the assumption that the age-related loss of neurons can contribute to the development of the disease.

[1], [2], [3], [4], [5], [6], [7]

Pathogenesis of Parkinson's Disease

The pathomorphological basis of Parkinson's disease is a decrease in the number of dopamine-producing neurons of a black substance and, to a lesser extent, a ventral tire. Before these neurons die, eosinophilic cytoplasmic inclusions, called Levi bodies, are formed in them. The loss of more than 80% of the pigmented dopaminergic neurons of the black substance leads to a significant decrease in the number of presynaptic dopaminergic endings and, respectively, the zones of dopamine re-uptake and a decrease in the activity of tyrosine hydroxylase, as well as a decrease in the level of dopamine in the shell. To a lesser extent, dopaminergic innervation is deprived of the caudate nucleus, the contiguous nucleus, the frontal cortex, which receive innervation primarily from the ventral tire. The level of dopamine metabolites, such as homovanic acid or dihydroxyphenyl acetate, is reduced to a lesser degree than the level of dopamine itself, indicating an increase in the dopamine circulation and an increase in the activity of the remaining dopaminergic endings. Postmortem studies have shown that the number of dopamine D1 and D2 receptors in untreated patients with Parkinson's disease is increased. However, in patients undergoing treatment, such changes are not detected either because of prolonged drug stimulation of these receptors, or because of secondary changes in postsynaptic striatal neurons.

Due to a decrease in the release of dopamine, the B2 mediated receptor mediated inhibition of the striatum, which leads to hyperactivity of the indirect pathway. At the same time, the stimulation of the striatum mediated by D1 receptors is weakened, which leads to a decrease in the activity of the direct pathway. According to this model, patients with Parkinson's disease have difficulty in performing tasks related to the implementation of sequential movements, due to a decrease in the function of the direct path, and there is an excessive inhibition of accompanying movements, leading to oligokinesia and bradykinesia, due to increased activity of the indirect pathway.

With Parkinson's disease, the number of noradrenergic neurons in the blue spot decreases, and then the noradrenergic endings in the anterior parts of the brain. Animals with experimental parkinsonism showed an increased circulation of acetylcholine in the brain, but these changes were not confirmed in the study of patients with Parkinsonism. In patients with Parkinson's disease antagonists of muscarinic cholinergic receptors (cholinolytics) reduce the severity of symptoms, especially tremor.

In untreated laboratory animals with experimental parkinsonism, there was a decrease in the number of GABA receptors in the outer segment of the pale sphere and its increase in the inner segment of the pale sphere and the black substance. These data correspond to the assumptions of indirect pathway hyperactivity and the hypoactivity of the direct pathway in Parkinson's disease. GABA-receptor agonists can have a beneficial effect on Parkinson's disease, weakening the stress caused by the increase in symptoms. A study of the brain in patients with Parkinson's disease noted a decrease in the concentration of serotonin, but there is no conclusive evidence of a decrease in the number of neurons in the nuclei of the suture. In patients with Parkinson's disease, suffering from depression, serotonergic markers in the cerebrospinal fluid are lower in serotonergic markers than in patients without depression. Therefore, antidepressants that affect the serotonergic system are often used to treat affective disorders in Parkinson's disease.

A high concentration of enkephalin and dinorphine was found in the striatum. The first is mainly concentrated in GABA-ergic projection neurons of the indirect pathway, the second - in GABA-ergic neurons of the direct pathway. Although a high concentration of opioid and cannabinoid receptors was detected in the pallid sphere and black substance, studies of the efficacy of opioids and cannabinoids in parkinsonism were practically not carried out.

Although glutamate, substance P, neurotensin, somatostatin, cholecystokinin can also be involved in the pathogenesis of Parkinson's disease, there are currently no means that selectively affect these systems. From the theoretical point of view, the inhibition of glugamatergic transmission in the corticostrial or subthalamopallidar pathway can be effective in Parkinson's disease. However, at the present time, clinical studies are under way to test this hypothesis.

Selective sensitivity. The death of dopaminergic neurons in Parkinson's disease can be associated with several factors. First, with the age-related decrease in the number of dopaminergic cells. Both postmortem pathomorphological studies and positron emission tomography data show that a natural decrease in dopaminergic neurons and their endings occurs in a person with age. This phenomenon, combined with the effects of genetic and external factors, can explain the increase in the incidence of Parkinson's disease with age. It is possible that some people have a lower number of dopaminergic neurons since birth. Accordingly, it can be assumed that even as a result of normal aging, the number of neurons will drop below the threshold value, which causes the development of symptoms. Others have genetic factors that accelerate the age-related death of neurons. It is noted that in patients who experienced the effects of some toxins or infectious agents that reduce the number of dopaminergic neurons in their young years, the symptoms may increase with age, probably as a result of the "superposition" of the process of age-related neuronal death.

Only in a small number of patients with Parkinson's disease is the family type of the disease, while the genetic defect can be inherited by an autosomal dominant type or transmitted with the mitochondrial genome from the mother. In several families with an autosomal dominant type of inheritance of parkinsonism, a mutation in the alpha-sinuclein gene was detected. Subsequently, it was found that alpha-sinuclein is the main component of Levy's bodies. In this regard, it is suggested that the accumulation and pathological aggregation of alpha-synuclein can be a key factor leading to cell death through stimulation of the mechanisms of programmed cell suicide (apoptosis). In this case, the accumulation of alpha-synuclein can be associated with genetically determined changes in its structure, posttranslational pathological changes in its conformation, or a violation of the function of systems that prevent the accumulation of proteins in the cell and ensure their metabolic degradation. Much of the patients with Parkinson's disease are diagnosed with mitochondrial dysfunction, which can promote increased formation of free radicals, which are a by-product of inefficient energy metabolism. In a black substance, a high concentration of antioxidant substances ("cleaners" of free radicals), such as glutathione and catalase, is normally found, but in Parkinson's disease their content in the brain is significantly reduced. It is possible that the imbalance in the formation and neutralization of free radicals plays an important role in the pathogenesis of this disease.

Exogenous factors. The influenza pandemic that broke out after the First World War was accompanied by rare cases of Enconomo encephalitis. These patients developed an acute Parkinsonian syndrome, which was often accompanied by additional manifestations, such as oculogic crises. In other patients, similar manifestations developed months or years after the acute phase of the disease. In the pathomorphological study of the brain in patients with postencephalitic parkinsonism, neurofibrillary glomeruli were detected in the black substance, and not the Levy body, characteristic of Parkinson's disease. It is believed that the causative agent of the disease was a virus that could penetrate into the neurons of the black substance and lead to their destruction, causing Parkinson's syndrome immediately or delayed. This virus was the cause of a significant number of cases of parkinsonism since the 1930s. In the following, cases of parkinsonism caused by encephalitis of another etiology were described.