Modulation of Synaptic Transmission and Analysis of Neuroprotective Effects of Valproic Acid and Derivates in Rat Embryonic Motoneurons

Abstract

Amyotrophic lateral sclerosis is a devastating motoneuron disorder for which no effective treatment exists. There is some evidence for neuroprotective effects of valproic acid (VPA). The beneficial effects, however, are limited due to the adverse effects of VPA. To overcome this problem, a number of VPA derivates with fewer side effects have been synthesized. In the present study, we investigated the viability of highly purified embryonic motoneurons cultured on glial feeder layers, composed of either astrocytes or Schwann cells, or in monoculture, in presence of VPA and its three derivates 3-propyl-heptanoic acid (3-PHA), PE-4-yn enantiomers (R- and S-PE-4-yn). An excitotoxic stimulus, kainate (KA), was added at day in vitro 9 (DIV9) and the neuroprotective effect of either simultaneous incubation (DIV9) or pre-incubation (DIV1) of VPA and its derivates was tested. The survival of motoneurons under simultaneous application of KA and VPA derivates was not remarkably increased. Pre-incubation with VPA and even more with the derivates before the addition of KA, however, significantly reduced their vulnerability against the KA-induced neurotoxic effect. Our data suggest that the neuroprotective capacities of VPA and its three derivates tested here drastically increase when they are added several days before KA. Most prominent neuroprotective effects were seen for the PE-4-yn enantiomers. Patch-clamp experiments revealed an antiexcitotoxic effect of the S-PE-4-yn enantiomer that reduces the frequency of postsynaptic currents and enhances the inhibitory postsynaptic transmission dependent on the co-culture condition.

Synergistic association of resveratrol and histone deacetylase inhibitors as treatment in amyotrophic lateral sclerosis

“…VPA treatment reduced neurotoxicity in motor neuron cellular models of ALS (Ragancokova et al, 2010;Jiang et al, 2016;Gyawali et al, 2022). In vivo, oral administration of VPA at the antiepileptic dose of approximately 500 mg/kg/day increased lifespan by 8% without delaying the disease onset in SOD1(G93A) male mice (Sugai et al, 2004).…”

Current Therapy of Drugs in Amyotrophic Lateral Sclerosis

“…Gacyclidine, a high affinity non-competitive NMDA receptor antagonist, delayed locomotor function impairment, improved survival by 4.3%, partially preserving body weight with a low dose (0.1 mg/kg) [ 47 ]. Valproic acid, histone deacetylases (HDAC) inhibitor, protects cultured neurons against glutamate or kainite-induced excitotoxicity [ 48 , 49 ] and reduces apoptosis [ 50 ]. Combination treatment of valproate and lithium postpones disease onset, lessens neurological deficits and extends survival in ALS mice [ 51 ].…”

Therapeutic neuroprotective agents for amyotrophic lateral sclerosis

“…Along with anti-excitotoxic effects, HDAC inhibitors have anti-inflammatory and neurotrophic properties. The HDAC inhibitor valproic acid (VPA) protects against glutamate or kainite-induced excitotoxicity in cultured neurons [66, 67] and achieves neuroprotection by reducing the number of apoptotic cells [68] and upregulating Bcl-2 [69]. Combined valproate and lithium treatment delays disease onset, reduces neurological deficits, and prolongs survival in ALS mice [70].…”