Antioxidants l-carnitine and d-methionine modulate neuronal activity through GABAergic inhibition

Abstract

Antioxidants are well known for their neuroprotective properties against reactive oxygen species in cortical neurons and auditory cells. We recently identified L-carnitine and D-methionine to be among agents that provide such protection. Here, we investigated their neuronal modulatory actions. We used cultured neuronal networks grown on microelectrode arrays to assess the effects of L-carnitine and D-methionine on network function. Spike production and burst properties of neuronal networks were used as parameters to monitor pharmacological responses. L-Carnitine and D-methionine reduced spike activity with 100 % efficacy with EC 50 values of 0.22 (±0.01) mM and 1.06 (±0.05) mM, respectively. In the presence of 1.0-40 lM of the GABA A antagonist bicuculline, the sigmoidal concentration-response curves of both compounds exhibited stepwise shifts, without a change in efficacy. Under a maximal bicuculline concentration of 40 lM, the EC 50 increased to 3.57 (±0.26) mM for L-carnitine and to 10.52 (±0.97) mM for D-methionine, more than a tenfold increase. The agonist-antagonist interactions with bicuculline were estimated by Lineweaver-Burk plot analyses to be competitive, corroborated by the computed dissociation constants of bicuculline. For both compounds, the effects on the network burst pattern, activity reversibility, and bicuculline antagonism resembled that elicited by the GABA A agonist muscimol. We showed that the antioxidants L-carnitine and D-methionine modulate cortical electrical spike activity primarily through GABA A receptor activation. Our findings suggest the involvement of GABAergic mechanisms that perhaps contribute to the protective actions of these compounds.

Attention deficit/hyperactivity disorder as an associated feature in OCTN2 deficiency with novel deletion (p.T440‐Y449)

“…L‐carnitine has similarly been shown to have neuroprotective and antioxidant roles. L‐carnitine was shown to modulate cortical electrical spike activity in cultured neuronal networks primarily through GABAA receptor activation . L‐carnitine has been shown to inhibit increases in glutamate, glycine, and superoxides and to decrease cardiolipin after hypoxia‐ischemia in newborn rats .…”

Levocarnitine induced seizures in patients on valproic acid: A negative systematic review

“…It is believe that most of this neuroprotective effect stems from preservation of mitochondrial function, avoiding free radical production and excitotoxic pathways [25][26][27][28]. Some animal studies also suggest a neurotransmission inhibitory function to L-carnitine [29,30], potentially via a GABA mediated pathway [30]. Despite this data however, few animal studies have recorded some potential excitatory effects of the levorotary enantiomer of carnitine (i.e.…”

“…L-carnitine) [31][32][33]. A rat model displayed a cholinergic mediated acetyl-L-carnitine mediated epileptiform discharges [30]. Furthermore, a mice kindling model pointed to the potential of acetyl-L-carnitine supplementation to lead to decreased dopamine levels [32].…”

Advances in D-Amino Acids in Neurological Research

“…D-Methionine has no known activity in the brain but protect against toxicity of a variety of drugs as well as protecting against noise-induced hearing loss [ 71 , 155 , 156 ]. A recent study found that D-methionine is transported into the brain using system L and the Asc transporter [ 72 ].…”