Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder

Abstract

Background Valproic acid (VPA), used for treating bipolar disorder (BD), is teratogenic by inhibiting histone deacetylase. In unanaesthetized rats, chronic VPA, like other mood stabilizers, reduces arachidonic acid (AA) turnover in brain phospholipids, and inhibits AA activation to AA-CoA by recombinant acyl-CoA synthetase-4 (Acsl-4) in vitro. Valnoctamide (VCD), a non-teratogenic constitutional isomer of VPA amide, reported effective in BD, also inhibits recombinant Acsl-4 in vitro. Hypothesis VCD like VPA will reduce brain AA turnover in unanaesthetized rats. Methods A therapeutically relevant (50 mg/kg i.p.) dose of VCD or vehicle was administered daily for 30 days to male rats. AA turnover and related parameters were determined using our kinetic model, following intravenous [1-14C]AA in unanaesthetized rats for 10 min, and measuring labeled and unlabeled lipids in plasma and high-energy microwaved brain. Results VCD, compared with vehicle, increased λ, the ratio of brain AA-CoA to unesterified plasma AA specific activities; and decreased turnover of AA in individual and total brain phospholipids. Conclusions VCD’s ability like VPA to reduce rat brain AA turnover and inhibit recombinant Acsl-4, and its efficacy in BD, suggest that VCD be further considered as a non-teratogenic VPA substitute for treating BD.

The ACSL4 Network Regulates Cell Death and Autophagy in Diseases

“…Moreover, since ACSL4 expression and activity are regulated by multiple regulators and different PTMs, derivatives of different inhibitors and inhibitors of these modification pathways can competitively inhibit ACSL4 expression. For example, valnoctamide, a non-teratogenic amide derivative of valproic acid, can non-competitively inhibit the activation of AA-CoA by ACSL4 and is suggested to be a therapeutic drug for bipolar disorders [ 178 , 179 ].…”

Valproic Acid and Its Amidic Derivatives as New Antivirals against Alphaherpesviruses

“…VCD is the primary amide of valnoctic acid and a constitutional isomer of VPD. Actually, it is a racemic compound which encompasses four stereoisomers, all of them showing a higher anticonvulsant efficacy in rodent models of epilepsy in comparison to VPA (about 3 to 10 times higher) [62,63]. In particular, the stereoisomer (2S,3R)-VCD stands out for having a greater oral clearance and a shorter half-life [52,64].…”

An update on the therapeutic implications of long-chain acyl-coenzyme A synthetases in nervous system diseases

“…Ferroptosis has been shown to be involved in the neuronal damage, aberrant electrical brain activity ( Shao et al, 2020 , 2022 ; Chen et al, 2022 ), and the progressive death of motor neurons ( Moujalled et al, 2021 ; Wang T. et al, 2022 ). Therefore, targeting ferroptosis-related protein ACSL4 may shed new light on the therapy of some other CNS diseases, including epilepsy ( Kahn-Kirby et al, 2019 ; Mao et al, 2019 ; Shao et al, 2020 , 2022 ; Yang et al, 2020 ; Chen et al, 2022 ), ALS ( Moujalled et al, 2021 ; Wang T. et al, 2022 ), cerebral malaria ( Liang et al, 2022 ), bipolar disorder ( Modi et al, 2014 , 2017 ), and sepsis-associated encephalopathy ( Wang J. et al, 2022 ). For example, mood stabilizer valproic acid and chiral isomer valnoctamide have been shown to take effect in the treatment of bipolar disorder by inhibiting recombinant ACSL4, brain AA turnover in brain phospholipids, and AA activation to AA-CoA ( Modi et al, 2014 , 2017 ).…”