New Potential of Memantine for Treatment of Cerebral Ataxia Uncovered
Together with British colleagues, Russian scientists proposed to treat severe and fatal disease known as spinocerebellar ataxia with memantine, a drug currently used for Alzheimer's disease. The drug blocks glutamate receptor proteins, thus preventing overexcitation and death of cerebellar neurons, and then reversing their pathological changes. The study was published in the International Journal of Molecular Sciences.
Spinocerebellar ataxias are a group of incurable hereditary neurological diseases that manifest themselves by degeneration in the cerebellum and other parts of the nervous system. Neurons die, and the patient's condition slowly deteriorates. It all begins with the clumsiness of movement, followed by a noticeable loss of coordination. Eventually the patients lose the ability to move, have difficulties in feeding and breathing, and finally die of respiratory failure.
The spinocerebellar ataxias develop due to a mutation in the genes and thus in the structure of the proteins encoded by them making them toxic for the cell. This leads to the disruption of several complex electrochemical processes that ensure the transmission of nerve impulses in the central nervous system. One of them is the disruption of the timely utilization of glutamate. This substance performs a signaling role in the brain, activating nerve cells. Therefore, excessively long exposure to glutamate can cause overexcitation of the neuron and its death. Cells whose main function is the capture of the glutamate accumulating in the intercellular space during neuronal activity, are particularly affected. In the cerebellum, these are specialized astrocytes, called Bergmann's glia.
"We assumed that blocking glutamate receptors would help protect these cells from damage. So we decided to try one of the proven drugs, memantine. It is used in the treatment of Alzheimer's disease, but could also potentially be suitable for the therapy of spinocerebellar ataxia,"—says Anton Shuvaev, head of the Research Institute of Molecular Medicine and Pathobiochemistry at the Krasnoyarsk State Medical University.
Scientists from Immanuel Kant Baltic Federal University (Kaliningrad), Voyno-Yasenetsky Krasnoyarsk State Medical University (Krasnoyarsk), Siberian Federal University (Krasnoyarsk), and Bristol University (UK) tested the hypothesis by experimenting with mice suffering from ataxia. The authors mimicked the disease using their newly developed model of Bergmann glia damage: mice were injected into the cerebellar cortex with viral particles containing sequences encoding an ion channel that opens when exposed to light. The procedure seems to simulate the effects of glutamate. This model reproduces the phenomena common to many cerebellar neurodegenerative conditions, which is very important for testing pharmacological developments in this scientific area.
Treatment of mice with cerebellar dysfunction with memantine resulted in not only stopping but also reversing pathological changes in Bergmann's glia. Thus, the thickness of their processes decreased and their length increased, looking more as it does in healthy brain. This indirectly led to a slowing of the death and normalization of the central neurons of the cerebellum—the Purkinje cells. Purkinje cells play a key role in the cerebellum, which is responsible for coordinating movements and maintaining balance. Thus, memantine protects them from fatal overexcitation.
"Our results prove that memantine could be a promising neuroprotective drug for patients with spinocerebral ataxia. We plan to investigate its effect in genetically modified mice created as a SCA1 model. With successful completion of the studies and confirmation of our hypotheses regarding this drug, we hope to significantly increase the life expectancy of such patients,"—says Sergey Kasparov, professor at Bristol University and consultant professor at Immanuel Kant Federal University.
Provided by Immanuel Kant Baltic Federal University