Stroke is caused when there is restricted flow of blood to some parts of the brain, which starves the brain cells of oxygen and glucose. This leads to death of brain cells, also called neurons, which cannot be fully replaced after they are lost. The oxygen and glucose-starved cells accumulate ‘lactate’ in the spaces between neurons. Lactate is a metabolic substance found in human body, it is a component of the substance, lactic acid that gives a sour taste to curd.
Prof Sujit K. Sikdar and his group at the Molecular Biophysics Unit, IISc, Bangalore are focussed on understanding various aspects of neurons and astrocytes (brain cells that support neurons) during disease states by measuring their activity using electrophysiological techniques. Recently, they have tried to answer the question whether lactate produced during stroke has a protective role in reducing death of neurons.
Neurons talk to each other via electrical signals and thus control the functions of all of our body parts. So how does this happen? Neurons have specialised ‘gates’ called ‘channels’ on their membrane, which allow select ions to pass through i.e. to enter or leave the cell. TREK1 is one such channel, regulating the flow of potassium ions out of the neurons, to maintain their normal functional state.
Lactate accumulating during stroke is known to protect neurons, by preventing the excess release of chemicals that initiate electrical signalling. This prevents adjacent neurons from firing unnecessarily, getting damaged and then dying, thus reducing the neurological deficits of stroke. Prof Sikdar’s students, Aditi Banerjee and Swagata Ghatak are studying the interaction of lactate with TREK1 channels in the context of stroke.
According to Banerjee, both lactate and TREK1 channels have been independently proven to protect neurons during stroke. This made them wonder whether lactate and TREK1 channels possibly worked together to protect neurons. They investigated this, by recording the activity of a single TREK1 channel and measuring whole cell TREK1 current in astrocytes in the presence of lactate using patch clamp technique.
“Astrocytes are a cleaner system than neurons where TREK1 currents can be easily isolated and recorded. We used astrocytes as they express TREK1 channels to a much larger extent than neurons,” explains Banerjee.Their results confirmed that TREK1 channel activity increased with increase in lactate concentration. Further, Ghatak explored the nature of this interaction between lactate and TREK1 channel and found a single amino acid (i.e. histidine at position 328 in the TREK1 protein chain) to be the crucial site for this interaction. She discovered that without this particular amino acid at the site, the lactate - TREK1 channel interaction was lost, inhibiting the protection of neurons.
Furthermore, Banerjee observed that, in response to lactate, astrocytes produce more TREK1 protein and increase TREK1 activity. Once they confirmed that lactate and TREK1 do interact, they wanted to verify whether this interaction was indeed responsible for neuroprotection in stroke. So next, they analysed the effect of lactate on neuronal death in the hippocampus, an area of the brain most susceptible to stroke, also involved in memory formation. It was found that lactate reduced the number of dying neurons, while failing to do so in presence of TREK1 channel blockers which inhibit channel activity. Furthermore, lactate also required the presence of healthy astrocytes to prevent death of neurons.
All these findings led to one important question, “Can lactate be used for treating stroke?” The current treatment against stroke includes anticoagulant therapy, antiplatelet therapy, and thrombolytic therapy (all of them serving to prevent or remove the blood clots blocking blood supply). However, several studies have reported serious drawbacks in these methods. Since, lactate is a physiological metabolite found in the body having a protective effect on brain cells, it has been proposed as a novel and ideal therapeutic agent to combat stroke. Even so, “Clinical trials are a long way from here. It is too early to comment whether lactate administration will be more effective than the current treatment for stroke. More experimental and clinical studies need to be done, before we can safely administer lactate to a patient suffering from stroke,” states Banerjee.
About the scientists:
Dr. Sujit K Sikdar is a Professor at the Molecular Biophysics Unit, Indian Institute of Science, Bangalore. He has numerous research publications and several awards to his credit including the prestigious Victor-Hasselblad Foundation Research Grant. His students, Dr. Swagata Ghatak and Ms. Aditi Banerjee (pursuing Ph.D at IISc) are involved in the research projects discussed in this article.