Articles

Injury to myelinated axons in the CNS often has a devastating outcome in terms of neuronal loss, with accompanying loss of function.

Damage to the nervous system may result from traumatic injury, such as penetrating or blunt trauma, stroke, or neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), diabetic neuropathy or senile dementia. Oxidative stress is implicated in the pathogenesis of many of these conditions, and the possible use of antioxidants of numerous chemical families has been extensively explored.

Injury to myelinated axons in the CNS often has a devastating outcome in terms of neuronal loss, with accompanying loss of function. Part of the damage occurs immediately, whereas part is delayed and leads to the death of neurons that escaped the direct insult.

Neurodegenerative diseases and disorders are commonly associated with ongoing neuronal loss in the CNS. Following the loss of neurons caused by primary risk factors, secondary neuronal loss is mediated by self-compounds, such as glutamate, nitric oxide or reactive oxygen species, that exceed their physiological concentrations. These compounds are implicated in various types of neurological disorders and acute CNS injuries. Destructive components common to neurodegenerative diseases have also been identified in autoimmune diseases such as multiple sclerosis. In this disease, myelin damage in the CNS is accompanied by subsequent neuronal loss.

The cerebroprotective effect of Cereprotex (Patent pending – Cereprotec Inc. www.cereprotec.com ) (2,4,6,8-tetramethyl-2,4,6,8-tetraazabicyclo[3.3.0]-octane-3,7-dione) , previously known as (CombiCNS1), was assessed in a model of closed head injury in mice. This type of trauma produces brain edema (i.e. increase in water content), breakdown of the blood brain barrier (BBB) and functional impairment. The effect of treatment with Cereprotex, administered 1 h after injury on brain edema and on neurobehavioral function was assessed 24 h later. While spontaneous improvement of function was observed in 2 mice out of 10 (20 %) in the control, non-treated group, treatment with Cereprotex resulted in the improved recovery of 5 mice out of 9 (55.5 %).

Glycoluril, 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione, and derivatives thereof, also termed bicyclic bisureas of the octane series, have been described as useful for treating psychic disorders (US 3,966,742; US 4,004,013) and ischemic heart diseases (US 4,571,403). Methods for the synthesis of glycoluril derivatives has also been described (US 3,966,742; US 4,004,013; Chegaev et al., 2001; Kostyanovsky et al., 2002; Kravchenko et al., 2000).

The capability of glycoluril derivatives to exhibit simultaneously both hydrophilic and lipophylic properties is responsible for the physiological action of these compounds: on one hand, they can easily penetrate the body and, on the other hand, readily overcome the hematoencephalitic barrier (Chegaev et al., 2001), also known as blood-brain-barrier (BBB).

A well known representative of the glycoluril derivatives is the compound named mebicar (2,4,6,8-tetramethyl-2,4,6,8-tetraazabicyclo[3.3.0]-octane-3,7-dione), used as tranquilizer since 1979. Mebicar exhibits extremely low toxicity, does not cause complications and side effects, does not suppress working ability and can be taken under any conditions by people of all ages. Mebicar is not metabolized and leaves the organism within 24 hours.

Another known representative of the glycoluril derivatives is albicar (2,6-diethyl-4,8-dimethy-2,4,6,8-tetraazabicyclo[3.3.0]-octane-3,7-dione, also described as psychotropically active and candidate for use as tranquilizer (Kostyanovsky et al., 2002).

US 4,004,013 and US 3,966,742 disclose medicinal preparations comprising 2,4,6,8-tetramethyl-2,4,6,8-tetraazabicyclo[3.3.0]-octane-3,7-diones for treating psychic disorders. US 4,571,403 discloses mebicar for treatment of ischemic heart disease.

Previous studies by the present inventor and colleagues have shown that mebicar exerts a protective action on some parameters of body function under the influence of extreme conditions such as stress and hypoxia, within a wide dosage range (100-1000 mg/kg), without affecting the muscle tone, movement coordination or working capacity of tested animals (Zimakova et al., 1980). Mebicar was also shown to change the balance of neuroactive amino acids in the animal’s brain by raising the content of gamma-butyric acid (Zimakova et al., 1982), and to exhibit a protective action in experimental arrhythmias (Kamburg and Zimakova, 1982). Mebicar was further shown to produce an antishock action and to normalize acid-base and oxygen homeostasis (Zimakova et al., 1984). Mebicar was also shown to increase the myocardial contractility, to exert a slight effect on the cardiac rhythm and to dilate the peripheral arteries, and the cardiac stimulating effects were attributed to the involvement of mebicar in the myocardial metabolism (Kamburg, 1990). Authors have developed experiment using mebicar (2,4,6,8-tetramethyl-2,4,6,8-tetraazabicyclo[3.3.0]-octane-3,7-dione) in form of generic formulation Cereprotex.

The present study describes the neuroprotective effects of Cereprotex (2,4,6,8-tetramethyl-2,4,6,8-tetraazabicyclo[3.3.0]-octane-3,7-dione) a well known formulation of mebicar used as tranqualisers since late 1970-s. Models of traumatic and hypoxic brain injury in mice and rats were used to assesses these effects.