A.P. Khokhlov, M.D., Professor.

Progress in clinical neurology that loomed in the 1970s did non develop in the next decades, however, and this field of medicine is currently stagnant.

One could easily enumerate the diseases that have "satisfactory" pathogenic therapy.

There is as yet no definite pathogenesis concept at the molecular level for the absolute majority of neurologic deficiencies, this is why treatment is frequently symptomatic except for hereditary pathology of the nervous system. The primary product of the mutant gene was identified in 105 nosologic forms; in these instances the pathogenesis is clearly determined, therefore effective preventive (for example, in phenylketonuric oligophrenia) or therapeutic (Wilson’s disease) measures were worked out.

But even in this field there are numerous unresolved problems. The therapy of chromosomal anomalies is practically inexistent even though the pathogenesis of some of these has been studied in sufficient detail (Down’s disease).

Meanwhile, advances in neurochemistry and neurobiology forming the foundation of clinical neurology are immense and, based on progress made, it would not be difficult to revise the pathogenesis concept of the majority of nervous diseases.

On the other hand, we gained clinical experience of using metabolic therapy preparations (in the form of food additives) which should facilitate a rapid introduction of new pathogenic drugs.

Until recently, present-day pathogenesis hypotheses were of universal nature and explained the decay of nerve cells in most neurologic disorders irrespective of the localization and, frequently, of etiologic factors.

Thus, the "glutamate" hypothesis considered neurocyte impairment as a result of hyperactivation of N-methyl-D-aspartate (NMDA) receptors which causes accumulation of excess calcium in the cell cytosol. In this case, an increase in cation level occurs in two ways:

1) through the calcium channel system of NMDA receptors;

2) by activating the phosphoinositide cycle with calcium recovery from the endoplasmic reticulum.

Under physiologic conditions, the activation of NMDA receptors and triggering of a cascade of phosphoinositide cycle reactions increase cell adaptation possibilities, initiate a lasting modification of ion conductivity, expression of key genes, etc. Yet, significant excess of calcium paralyzes the nerve cell function. Accumulating in mitochondria, the ion contributes to a dissociation of conjugate tissue breath processes and oxidative phosphorylation by restricting thereby the energetic neurocyte potentialities and stimulating lipid peroxidatic oxidation processes (LPO).

Concurrently, the activation of Ca++-dependent proteinases and hydrolases rapidly produces macromolecule degradation which eventually makes the cell unviable.

Can the cell decay be prevented under these conditions?

According to the glutamate hypothesis, this is theoretically possible. To achieve this, it is required to:

1) eliminate excessive amino acid in the cell and extracellular space of the brain;

2) decrease the affinity of glutamic receptors with the ligand;

3) use new therapeutic drugs, amino acid antagonists;

4) effect a calcium metabolism correction.

However, despite the obvious advisability of swift testing and introduction of drugs and treatment techniques in clinical neurology, there is growing skepticism with regard to the effectiveness of new methods of treatment.

Thus, drugs of the first group, glutamatdehydrogenase activators that decrease the glutamic acid level were tested without any result on 40 patients with amyotrophic lateral sclerosis (ALS) where the role of glutamate in central and peripheral motoneuron was considered to be proven (7).

The testing of rilosol (7), antagonist of dicarboxilic acid, was more successful. However, due to its insignificant therapeutic effect, this preparation cannot be considered basic in treating the above-mentioned severe disease.

Glycine and treonine, 3rd group drugs, showed negative results in some tests (15).

Accordingly, the value of the glutamate hypothesis in degenerative disorders is questionable now. On the other hand, it was reported about the expediency of the use of glutamatergic drugs in subcortical degenerations and parkinsonism (10).

Our studies have not confirmed the glutamate hypothesis either. The application of amino acids with a ramified chain in the majority of degenerative diseases did not produce reliable positive results.

In experiments on animals it was clarified, however, that the activity of glutamatdehydrogenase increased after Aminocomposit introduction in subcortical structure nuclei, but not in the cerebral hemispheres, cerebellum or spinal cord neurons.

Based on the results obtained, the amino acid compound (Aminocomposit) was administered in patients with extrapyramidal disorders, the dosage being 1-2 g daily.

A manifest therapeutic effect was recorded in parkinsonism patients. Diminished extrapyramidal tonus and an increased amount of movements were observed already on the 3rd-4th day in 87% of patients with akinetic-rigid forms and in 68% of patients with rigid-trembling forms.

A decrease (by 30-60%) of the parkinsonian tremor rhythm amplitude occurred on the 10th-12th day and practically in all cases it was possible to cut (by 30-50%) the L-DOPA dosage.

The therapeutic effect lasted for several months after which a course of treatment was repeated.

Besides, an important favorable effect was achieved in treating degenerative subcortical diseases, for instance, in olivopontocerebellar degeneration. In 1.5 months, neurologic deficiency could be diminished by 70-85%. The drug proved effective in eliminating extrapyramidal symptoms in ICP patients.

The positive results obtained only indirectly confirm the adequacy of the glutamate hypothesis, however. The elimination of the direct toxic action of excessive glutamate on the mitochondrial and genetic cell apparatus was not accompanied, at least in the experiment, by a change in the calcium level and principal indicator of the activity of NMDA receptors.

On the contrary, studies conducted in the recent years point to a diminished (10) function of glutamatergic neurons in some subcortical diseases, including in parkinsonism patients. The administration of glutamatergic medications favorably influenced the pathologic process in the disease concerned.

To correct this deficiency, we developed the amino acid compound Neoprim that contains a minimum amount (less than 8%) of L-glutamic acid and possesses a powerful glutamatergic effect.

The application point of the drug was assessed by three methods:

1) biochemical: measurement of the affinity degree of hippocampus NMDA receptors with the ligand;

2) electrophysiologic studies of the phenomenon of prolonged potentiation (hippocampus sections);

3) change in EEG range and rhythm in animals with implanted electrodes.

An increase (by 1.2 times) of the affinity of receptors with glutamate was accompanied by a clear-cut change of the characteristics-parameters of glutamatergic synaptic transmission.

The drug produced a manifest exciting effect. Upon introduction (10 minutes later) an increase of responses amounted to over 300%. As the dose increased, responses trustworthily grew in number.

The increase of not only post-, but also presynaptic pop-spikes points to increased excitability of membranes, decreased excitability threshold of axons and neuron bodies.

Similar data were obtained following EEG investigations of the brain of animals (Fig. 1).

Fig. 1. EEG of a rabbit: prior to; 1 hour after intramuscular injection of Neoprim at a dosage of 25/kg.

Neoprim became a basic drug in treating a series of nervous system disorders, in particular, peripheral motoneuron, subcortical diseases, oligophrenia, etc. The course of treatment lasts 15-30 days in combination with other amino acid compounds. In a limited amount, the drug proved useful in treating patients with consequences of severe cerebral circulation impairment.

The treatment stretches over 10-15 days, the dosages being 5-10 mg/kg daily. The results as manifested in motor activity recovery are impressive.

The literature reports that a successful use of glycine amino acid in the therapy of patients with severe cerebral circulation impairment brought a first serious corroboration of the suggested hypothesis (2).

It is supposed that the mechanism of the anti-ischemic effect of glycine consists in inactivating NMDA receptors as a result of interaction between the amino acid and the glycine loci. Thereby, excessive calcium accumulation in the cell is prevented.

According to Ye. Gusev, glycine intake at a dosage of 1-2 g daily resulted in a rapid withdrawal of neurologic deficiency (2).

In all fairness it should be stated that 3 years before this report was published, Prof. Khokhlov’s team successfully used this amino acid in treating acute cerebral circulation impairment (ACCI) patients. However, because of the opposition of Prof. F.I. Gorbacheva, head of the clinic where the testing was carried out, the study had not won acceptance and the publication resulted only in the application for an inventor’s certificate No. 4120032 from June 25th, 1986.

Another aspect is the therapeutic effect of the said amino acid in cerebellar involvement. Reports on this problem were widely published and confirmed by a number of leading Russian clinics.

The mechanism of the action of the drug in question consists in regulating calcium metabolism by an increased release of active phosphoinositides. The amino acid was used as a solution at a dosage of 3-6 g a day. The treatment lasted 30-50 days. In this context, a decrease in ataxia and other clinical cerebellar impairment manifestations was reported already at the end of the first week following the beginning of treatment. Concurrently, a rise in the number of metabolites of the phosphoinositide cycle (5) was recorded.