Could lactate and L-acetylcarnitine lead us to new drug targets?

Drugs based on epigenetic and metabolic mechanisms that influence glutamatergic function and neuroplasticity may one day contribute to the treatment of depression, EPA Virtual 2021 was told.

L-acetylcarnitine (LAC) helps eliminate the products of oxidation, protects against excitoxicity and  is centrally involved in the transport of fatty acids into mitochondria.1 Through acetylation, it modulates expression of neurotrophins and of glutamate, via its effects on mGlu2.

So it is interesting that, compared with matched controls, patients with major depressive disorder (MDD) have decreased levels of LAC in plasma.1 Among patients with MDD, lower levels are associated with more severe depression and earlier age at onset.

But the lowest levels were in people who had failed at least two trials with standard antidepressants, and who might therefore be considered treatment resistant. Among these patients, lower plasma LAC was associated with a greater likelihood of reporting childhood trauma,1 Carla Nasca (Rockefeller University, New York, USA) said in her presentation on genetic modulation of glutamatergic function.

Mitochondria have a potential role in depression as epigenetic regulators of neuroplasticity 

 

Resilience enhancing and antidepressant effects

In animal models including the forced swim test, LAC has antidepressant effects through the epigenetic induction of mGlu2 receptors.2 Dr Nasca also presented evidence that LAC can enhance resilience in the social defeat stress model,3 and noted that exercise increases LAC levels, as well as hippocampal volume.

LAC and related central insulin resistance4 may be implicated in a subtype of major depression linked to metabolic dysfunction. Further work is required to characterize the LAC-deficient phenotype and understand who might benefit from treatment, but LAC is a promising target for the development of a new class of potentially fast-acting antidepressant drugs, the symposium heard.

Lactate is another substance implicated in the metabolic dysfunction that may contribute to certain types of depression. In animal models, its peripheral administration is accompanied by increased levels in the hippocampus and by antidepressant-like effects.5 These seem to depend on neurogenesis, Pierre Magistretti (King Abdullah University of Science and   Technology, Saudi Arabia) told the meeting.

 

Lactate and intercellular signaling

As well as being an energy substrate, lactate is an intercellular signaling molecule relevant to processes as diverse as synaptic plasticity and neurogenesis, expression of serotonin receptor genes, and astrocyte function, he suggested.

Interest in lactate also relates to the antidepressant effects of exercise, which increases lactate in the periphery and in the brain.

Astrocytes may play a role in coupling neuronal activity and energy consumption, with implications for neuroplasticity

Astrocytes, which interact metabolically with neurons, are implicated in depression: astrocyte gene expression levels are low in the postmortem brains of people who had MDD.

Lack of energy available to the brain may increase vulnerability to a range of insults, Professor Magistretti speculated. This could be relevant not only in psychiatry but also in neurodegenerative diseases such as Alzheimers.

There is hypometabolism with aging in general; and, in ApoE 4 carriers, decreased cerebral glucose utilization is evident even in people who asymptomatic.7

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References

1. Carla C et al. Proc Natl Acad Sci USA 2018; 115: 8627-8632

2. Nasca C et al. Proc Natl Acad Sci USA 2013;110: 4804-9

3. Nasca C et al. Biological Psychiatry 2019; 86: 483-91

4. Nasca C et al. Molecular Psychiatry 2020, June 15

5. Carrard A et al. Molecular Psychiatry 2018; 23:392-9

6. Hagenauer MH et al. PLoS One 2018 Jul 17 13(7) e0200003

7. Ryu JC et al.  Neurotherapeutics  2019; 16: 600-10

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