RESEARCH & TECHNOLOGY

• The role of lactate in ischemic cerebral stroke
• Tracking lactate at the ultrastructural level using correlated EM-NanoSIMS
• Investigating the effects of other potentially beneficial metabolites in stroke
• Effects of metabolites on inflammation and repair of the neurovascular unit

• The role of lactate in ischemic cerebral stroke

  The Hirt laboratory is studying the role of lactate in ischemia. They previously showed that administration of exogenous lactate improves the outcome after cerebral ischemia both in vitro and in vivo by reducing the extent of neural damage and neurological impairment.

  

  Using magnetic resonance spectroscopy to characterise in real time the fate of isotope-labelled hyperpolarised lactate injected intravenously after stroke, in collaboration with Jean-Noel Hyacinthe and Mor Mishkovsky at the CIBM-EPFL and HES-SO Geneva, they showed that labelled ¹³C-lactate rapidly reaches the ischemic mouse brain and is converted to pyruvate and CO₂. The underlying protective mechanism is presumably lactate acting as a metabolic energy substrate. The Hirt laboratory now aim to gain a deeper understanding of the fate of exogenously administered lactate and the mechanisms underlying its beneficial effects by exploring the possible cellular and molecular mechanisms using molecular and pharmacological approaches.

  

• Tracking lactate at the ultrastructural level using correlated EM-NanoSIMS

  To discover the cells and organelles that metabolise exogenously administered ¹³C-labelled lactate, the Hirt laboratory is evaluating an innovative technology called correlated EM-NanoSIMS in collaboration with Anders Meibom and Graham Knott at EPFL and Christel Genoud at the Electron Microscopy Facility of UNIL. The spatial resolution of this technique is extremely high as it combines isotope imaging and electron microscopy to enable the subcellular localisation of metabolic tracers. Preliminary results with ¹³C-lactate and NanoSIMS showed a ¹³C-signal in the swollen astrocyte end feet in the ischemic lesion that coincided with glycogen granules. Glycogen is a large polysaccharide of glucose and is a form of energy storage in glial cells in the brain.

• Investigating the effects of other potentially beneficial metabolites in stroke

  The Hirt laboratory is exploring the effect of gut metabolites on the brain barriers (the blood-brain barrier and the meninges) and the neurovascular unit in stroke. New evidence identifies the gut microbiota as a modulator of brain function in health and disease and recent studies implicate a role of the gut-brain axis in regulating neurological disorders including stroke. Host-microbiota interactions are particularly important for maintaining barrier homeostasis, and disruption of these interactions significantly affects the gut barrier as well as the brain barriers.

  

  Additionally, Lorenz Hirt and collaborators are investigating a possible neuroprotective role of beta-hydroxy-butyrate, a naturally occurring ketone body, in stroke. Ketone bodies, whose production is induced by fasting, can be used as alternate energy substrates by the brain. Interestingly, research has already shown a beneficial role of exogenous ketone body administration in epilepsy.

• Effects of metabolites on inflammation and repair of the neurovascular unit

  The Hirt laboratory has previously shown the impact of cerebral ischemia on the neurovascular unit by illustrating the spatiotemporal evolution of post-ischemic neuroinflammation. They have now extended their study to explore whether neuroprotective metabolites have an effect on neuroinflammation.

  

  Attempt of brain cells to repair the damage caused by experimental ischemia. In the lesion area, cell proliferation (magenta) occurs in and around a blood vessel (brown) that is enveloped by pericytes (cyan), three days after transient MCAO surgery. Cell nuclei are shown in gray.