Using lactate for stroke
Nishita Bhembre, May 31, 2016,
Stroke is caused when there is a restricted flow of blood to some parts of the brain, which starves the brain cells of oxygen and glucose. This leads to damage and 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 lactic acid that gives a sour taste to curd. Prof Sujit K Sikdar and his group at the Molecular Biophysics Unit, Indian Institute of Science (IISc), Bengaluru 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. Electrophysiological methods are used to assess the electrical properties of individual cells and biological tissues.
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.
Natural solution
Lactate, accumulated during stroke is known to protect neurons, by preventing the excess release of chemicals (termed neurotransmitters) that initiate electrical signalling.
This prevents adjacent neurons from firing unnecessarily, getting damaged and then dying as a consequence, thus reducing the neurological deficits of stroke. Few studies have even reported that lactate reduces size of infarct (a localised area of dead tissue) caused by stroke. Prof Sikdar’s students, Aditi Banerjee and Swagata Ghatak are engaged in studying the interaction of lactate with TREK1 channels in the context of stroke.
According to Aditi, both lactate and TREK1 channels have been independently proven to protect neurons during stroke by several studies. 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. This technique is used to record the current in patches of cell membrane (either attached to cell or excised).
“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 Aditi. Their results confirmed that TREK1 channel activity increased with increase in lactate concentration. Further, Swagata explored the nature of this interaction between lactate and TREK1 channel and a single amino acid (i.e., histidine at position 328 in the TREK1 protein chain was found 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 by means of lactate.
Furthermore, Aditi observed that, in response to lactate, astrocytes produce more TREK1 protein and there was increased TREK1 activity as well. These results were obtained using double immunofluorescence-staining studies, western blotting and quantitative PCR techniques. 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 requires the presence of healthy astrocytes to prevent death of neurons by excessive firing.
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 which serve 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 that has 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 Aditi.
(The author is with Gubbi Labs, Bengaluru)
Lactate is a metabolic substance found in human body. It is a component of lactic acid that gives a sour taste to curd. Prof Sujit K Sikdar and his group at the Molecular Biophysics Unit, Indian Institute of Science (IISc), Bengaluru 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. Electrophysiological methods are used to assess the electrical properties of individual cells and biological tissues.
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.
Natural solution
Lactate, accumulated during stroke is known to protect neurons, by preventing the excess release of chemicals (termed neurotransmitters) that initiate electrical signalling.
This prevents adjacent neurons from firing unnecessarily, getting damaged and then dying as a consequence, thus reducing the neurological deficits of stroke. Few studies have even reported that lactate reduces size of infarct (a localised area of dead tissue) caused by stroke. Prof Sikdar’s students, Aditi Banerjee and Swagata Ghatak are engaged in studying the interaction of lactate with TREK1 channels in the context of stroke.
According to Aditi, both lactate and TREK1 channels have been independently proven to protect neurons during stroke by several studies. 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. This technique is used to record the current in patches of cell membrane (either attached to cell or excised).
“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 Aditi. Their results confirmed that TREK1 channel activity increased with increase in lactate concentration. Further, Swagata explored the nature of this interaction between lactate and TREK1 channel and a single amino acid (i.e., histidine at position 328 in the TREK1 protein chain was found 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 by means of lactate.
Furthermore, Aditi observed that, in response to lactate, astrocytes produce more TREK1 protein and there was increased TREK1 activity as well. These results were obtained using double immunofluorescence-staining studies, western blotting and quantitative PCR techniques. 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 requires the presence of healthy astrocytes to prevent death of neurons by excessive firing.
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 which serve 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 that has 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 Aditi.
(The author is with Gubbi Labs, Bengaluru)
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