Valproic acid potentiates curcumin-mediated neuroprotection in lipopolysaccharide induced rats

Abstract

The etiology of neuroinflammation is complex and comprises multifactorial, involving both genetic and environmental factors during which diverse genetic and epigenetic modulations are implicated. Curcumin (Cur) and valproic acid (VPA), histone deacetylase 1 inhibitor, have neuroprotective effects. The present study was designed with an aim to investigate the ability of co-treatment of both compounds (Cur or VPA, 200 mg/kg) for 4 weeks to augment neuroprotection and enhance brain recovery from intra-peritoneal injection of (250 μg/kg) lipopolysaccharide-stimulated neuroinflammatory condition on rat brain cortex. Cortex activation and the effects of combined treatment and production of proinflammatory mediators, cyclooxygenase-2 (COX-2), APE1, and nitric oxide/inducible nitric oxide synthase (iNOS) were investigated. Neuroinflammation development was assessed by histological analyses and by investigating associated indices [β-secretase (BACE1), amyloid protein precursor (APP), presenilin (PSEN-1), and PSEN-2)]. Furthermore we measured the expression profile of lethal-7 (let-7) miRNAs members a, b, c, e, and f in all groups, a highly abundant regulator of gene expression in the CNS. Protein and mRNA levels of neuroinflammation markers COX-2, BACE1, APP, and iNOS were also attenuated by combined therapy. On the other hand, assessment of the indicated five let-7 members, showed distinct expression profile pattern in the different groups. Let-7 a, b, and c disappeared in the induced group, an effect that was partially suppressed by co-addition of either Cur or VPA. These data suggest that the combined treatment induced significantly the expression of the five members when compared to rats treated with Cur or VPA only as well as to self-recovery group, which indicates a possible benefit from the synergistic effect of Cur-VPA combination as therapeutic agents for neuroinflammation and its associated disorders. The mechanism elucidated here highlights the particular drug-induced expression profile of let-7 family as new targets for future pharmacological development.

Curcumin exerts protective effects against hypoxia‑reoxygenation injury via the enhancement of apurinic/apyrimidinic endonuclease�1 in SH‑SY5Y cells: Involvement of the PI3K/AKT pathway

“…These differences may be a result of the different research systems used: The previous study examined a virus system, while the present study investigated SH-SY5Y cells. consistent with our present research, a number of other studies have also confirmed that curcumin exerts biological activities via activation of APE1 (43,44). Subsequently, it was revealed that the knockdown of APE1 by transfection with APE1 siRNA reversed the curcumin-induced protective effects against OGd/R injury in SH-SY5Y cells, suggesting the contribution of APE1 to the neuroprotective effects of curcumin.…”

Morphological and Biochemical Features of Cerebellar Cortex After Exposure to Zinc Oxide Nanoparticles: Possible Protective Role of Curcumin

“…The anti‐inflammatory properties of Cur might result from inhibition of proinflammatory cytokines and COX‐2 involved in NF‐κB pathway. In line with our finding, Cur has been found to block the LPS‐mediated induction of COX 2 through inhibition of NF‐κB pathway (Kang et al, , Zaky et al, ). The biological effects of Cur are mainly derived from its ability to either bind directly to various proteins such as COX‐2 or its ability to modulate the intracellular redox state (Hong et al, ).…”

A Novel Combination of ω-3 Fatty Acids and Nano-Curcumin Modulates Interleukin-6 Gene Expression and High Sensitivity C-reactive Protein Serum Levels in Patients with Migraine: A Randomized Clinical Trial Study

“…In addition, curcumin is able to suppress IL-6 production in astrocytes located in CNS and downregulate proinflammatory mediators mRNA such as Monocyte Chemoattractant Protein-1 (MCP-1) [42]. Based on a study by Zaky et al, a combination of curcumin with valproic acid could synergistically potentiate neuroprotection effects in neuroinflammatory condition induced lipopolysaccharide in rat and improve recovery [43]. Additionally, curcumin can suppress the TNF-α, IL-6 and IL-1β gene expression, contributing to inflammatory and neurogenic pain [44].…”