GEROVITAL (GH3) Articles (III)The Antidepressive Effect and Action of Gerovital-H3®
(The Treatment Of Cognitive Impairment)
by Mircea Dumitru M.D., Ph.D.Depressive states and cognitive impairment in old people represent some of the most important issues in our contemporary life. According to DSM-III-R, even young people are suffering various forms of depression, their frequency being from 3% to 6%, but in old people the incidence is even greater occurring in 15% in men and 21% to 23% of women.
Brain Cells
Whereas almost all other human cells divide in a continuing chain, nerve cells do not multiply. Every day approximately 150,000 brain cells die and as we grow older, even more die daily. Brain cells are intricately connected in a very complicated network. While we lose many cells every day, we have an enormous reserve of cells in our brain that store information, facts and experiences. The impairment of the cognitive function is the expression of the functional and structural events that are changing with age: alterations of the neurotransmitter levels; the decrease of proteins and DNA synthesis and the decrease of membrane phospholipid synthesis.
Neurotransmitters are involved in facilitating the acquisition of information and memorizing facts. Among them, the cholinergic system plays a key role. The age related cholinergic impairment goes through other neurotransmitters producing additional effects on cognitive function (1).
Experiments have revealed that long-term memory is connected to the cortical protein synthesis and short term-memory to the hippocampus protein synthesis (2, 3).
Other possible targets of aging metabolic change occur in the nervous system, processes such as modifications of DNA, RNA and proteins, which in turn affect learning and memory (4).
Gerovital-H3® and Brain Cell Alterations
Gerovital-H3® and its hydrolysis products PABA and DEAE follow the neurotransmitters pathway. PABA represents the background of folic acid formation, through which its co-enzymatic structure, [tetrahydrofolic acid], has an essential roll in the pureness of pirimidine-tymine biosynthesis. Due to procaine's interaction with the membrane phospholipids, Gerovital-H3® is involved in the improvement of degenerative processes in old age.
Data indicates that Ca2+ regulation changes are constantly associated with brain aging and malfunctioning cells that could be due to the structural and functional capacity of the cellular membrane, Ca2+ connecting proteins, or energy-dependant systems that regulate Ca2+.
The various molecular systems that are regulating and maintaining the calcic homeostasis represent the final mutual path for the age-related brain changes (5). Gerovital-H3® interacts with various ionic channels by modu1ating the inter-cellu1ar processes of Na+, K + and Ca2+. By modu1ating the Ca2+ conductivity within the excitable biological structures, Gerovital-H3® maintains the intracellular calcium homeostasis. This is the pathway through which Gerovital-H3® restores the hypocampic neurons normal excitability, counteracting their increasing phenomena of the hyper polarization. The resu1ted ethanol amine of the second stage of procaine hydrolysis is the forerunner of the phosphodiethylethanolamine synthesis. Phosphodiethylethanolamine along with phosphatidylserine and phosphatidylcholine represent the ce1lu1ar membrane's structural phospholipids. As a resu1t of the consequent methylization, phosphotidilethanolamine is converted into phosphatidylcholine and through a reversible reaction with L-Serine creates phosphatidylserine (6).
In the aging process, we see a decrease of the membrane phospholipids synthesis with deep physiological consequences. Ethanol-amine from Gerovital-H3®- plays a role in restoring the structure and the physiological processes of the cell membrane.
Experimental data shows that under Gerovital-H3® treatment the level of the learning rate is higher, with a better emotional adjustment and orientation capacity.
"It has been shown that the best performances of monastic retention are of those groups treated with Gerovital-H3®, DEAE and PABA+EA (7)."
Gerovital-H3® and Clinical Studies
Polypathology and antidepressive drugs, (especially the tricyclic substances) in elderly people is counter-indicated due to the common acetylcholinic side effects.
In the group of MAO-I's medication (mono-amine oxidase inhibitors) a new treatment appeared with better general tolerance and without side effects- it was Gerovital-H3® (8, 9, 10, 11).
Zung did the first double-blind study comparing the effects of Gerovital-H3® administered i.m., versus Imipramine administered p.o. and versus placebo.(8)
He studied outpatients 60 years and older, who had mild depressive disorders of global severity. This was determined by using a Clinical Global Impression. The dosage of Imiprarnine treated patients during the 4-week treatment period showed a mean total dosage of 74,8 mg/day. The dosage of patients on Gerovital-H3® during the 4-week period of treatment showed a mean tota1 dosage of 2,022 mg.
Comparing Day 0 with Day 28 of all the variable measures in the Gerovita1 H3 treated group, the results indicated that the patients improved significantly on Clinical Globa1 Impression, and on the Anxiety Status Inventory and on the Self-rating Depression Scale (8). The results of this study show that using Clinical Global Impression and the Zung Self Depression Sca1e, the change scores obtained from ca1culating pre-treatment to post-treatment differences prove Gerovital-H3® to be superior to imipramine since the Gerovital-H3®/ placebo differences were significantly different, while the imipramine/ placebo differences were not.
Saka1is and Gershon using a maximum tota1 dosage of 1,350 mg of Gerovita1-H3 reported improvement in depressive symptomatology of their senile-arteriosclerotic patients studied (12). Ba1aceanu and al (13) in 1996 did a double-blind study in order to point out the antidepressive effect of Gerovital-H3®, to assess the clinical tolerance of the drug and the possible side effects. After a geronto-psychological screening from 1443 old people, and using DSM-III-R criteria, the authors selected 286 patients suffering from various forms of depression. They excluded patients with a marked decrease of visua1 and auditive acuity, severe pathology and depressive patients who already took antidepressive treatments.
Group 1 received Physiologica1 serum and Group 2 received Gerovital-H3® as follows; for 10 days 1 i.m. via1 in the morning, and for 11 more days 2 i.m. vials, one in the morning and one at noon. During the treatment one patient with organic depressive syndrome and a1cohol-dependent personality disorders presented psychiatric side effects, virulence, irritability and harm pretending tendencies.
In conclusion, the authors noted that the clinical tolerance was good. The assessment of the depressive state intensity using psychological methods proved statistically significant ameliorations after the treatment with Gerovital-H3®. The cognitive performances were better at the second examination in the group receiving Gerovital-H3® comparing with the group receiving physiological serum.
Gerovital-H3® and MAO
Mono Amine Oxidase (MAO) is mainly responsible for the degradation of biogenic amines and a MAO inhibiting effect brings about an increase of biogenic amines concentration at the synaptic level. It is known that Gerovital-H3® is a selective and reversible inhibitor of MAO (14). Hrachovec showed that Gerovital-H3 has an enhanced inhibiting action (87,4%) as compared to procaine hydroch1oride (64.9%) on MAO (15).
MacFarlane a1so demonstrated that Gerovital-H3® is a MAO inhibitor (16). These studies are particularly relevant in view of Robinson demonstrating a relationship between aging, MAO levels and central amines (17). Robinson found that MAO activity correlates highly with increasing age when studied in human brain, plasma and platelets. Women were found to have significantly higher mean platelet and plasma MAO activity than men.
Other mechanisms of Gerovital-H3® action are possible, these include: thyroxin-hydroxylasis activation through an alosteric effect determined by ions influx and inhibition of synaptic uptake (18). We know that repeated administration of MAO-I drugs depresses 5-HT 1 (the somato-dendritic auto receptors of serotoninergic neurons) determining an inhibition of synaptic occupation.
Gerovital-H3® is also a cholinergic activator through its hydrolysis products- diethylaminoethanol and ethanol amine, and can exert indirectly a modulating action on the other systems of neuromediators, an action which has a certain regional specificity. This assertion is based on the fact that there is an extensive distribution of monoaminergic terminations on the cholinergic neurons- the striatal cholinergic basal nuclear complex, which suggests several anatomic and functional interactions between these systems, interactions that often have double meaning (19).
Gerovital-H3® and Depression
Yau in a fundamental study summarized the mechanisms of Gerovital-H3® in depression (20):
Gerovital-H3® is a reversible and competitive inhibitor of MAO. Gerovital-H3® may function as an antidepressant by modifying the level of brain monoamines.
Compared with classic MAO-I, Gerovital-H3® is quite selective in inhibiting the oxidative desamination of certain important brain monoamines.
Due to the inhibition of Gerovital-H3® on the oxidative desamination of liver Tyramine and Tryptamine, the normal physiological function of liver MAO to inactivate excess amount of ingested or endogenously present toxic amines is not impaired, thereby eliminating the "hypertensive crisis" so typical of other MAO inhibitors.
Yau concluded that, in addition to being an efficacious drug in the treatment of depression, Gerovital-H3® seems to have some additional advantages in terms of its pharmacological effects and increased safety.Gerovital-H3®; Other Benefits
Scientific data proves that Gerovital-H3® is not on1y an effective antidepressant treatment, but it also stimulates cognitive functions, loco-motor activity and improves emotional stability.
Gerovital-H3® determines a central nervous system functional amelioration by the active neuro-mediating and balances equilibrium among neurotransmitters. Due to the inhibition of the generation of the super oxide radical, Gerovital-H3® is an anti-oxidant, a potent free radical quencher.
Gerovital-H3® is not only useful to treat depressive disorders in adults and elderly people but also to prevent them. Gerovital-H3® treatment is indicated to prevent degenerative processes and to retard the ageing process and to help prevent various forms of depression frequently associated with them. The incidence of depression in the elderly having utilized a long-term Gerovital-H3® treatment is far lower than in similar groups without any treatment.
Gerovital-H3® Dosages
Preventive treatment of chronic diseases, the ageing process and depression consists of 4 courses of 12 injections and 4 courses of 24 pills during one year; one course of 12 injections over 4 weeks (4 injections per week), a 4-week break then one course of 24 pills over 12 days (one pill twice daily between meals), a 2-week break and then the cycle is resumed.
Starting from the age of 40, the prophylactic treatment with pills on1y is recommended in a series of 25 tablets during the first 12 days, with an interval of 2 months; 1st day, one tablet/day, 2 hours after breakfast, increasing to the 12th day when 2 tablets per day are taken (2 hours after meals-10 AM and 4PM). There should be a series of 5 treatment courses in a year, which shou1d be increased to 6 per year for people over the age of 65.
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