Levetiracetam Ameliorates Doxorubicin-Induced Chemobrain by Enhancing Cholinergic Transmission and Reducing Neuroinflammation Using an Experimental Rat Model and Molecular Docking Study

Abstract

Cancer chemotherapy-induced cognitive impairment (chemobrain) is a major complication that affects the prognosis of therapy. Our study evaluates the nootropic-like activity of levetiracetam (LEVE) against doxorubicin (DOX)-induced memory defects using in vivo and molecular modelling. Rats were treated with LEVE (100 and 200 mg/kg, 30 days) and chemobrain was induced by four doses of DOX (2 mg/kg, i.p.). Spatial memory parameters were evaluated using an elevated plus maze (EPM) and Y-maze. Additionally, acetylcholinesterase (AChE) and the neuroinflammatory biomarkers cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed using brain homogenate. PharmMapper was used for inverse docking and AutoDock Vina was used for molecular docking. LEVE treatment significantly diminished the DOX-induced memory impairment parameters in both the EPM and Y-maze. In addition, the drug treatment significantly reduced AChE, COX-2, PGE2, NF-κB, and TNF-α levels compared to DOX-treated animals. The inverse docking procedures resulted in the identification of AChE as the potential target. Further molecular modelling studies displayed interactions with residues Gly118, Gly119, and Ser200, critical for the hydrolysis of ACh. Analysis of the results suggested that administration of LEVE improved memory-related parameters in DOX-induced animals. The ‘nootropic-like’ activity could be related to diminished AChE and neuroinflammatory mediator levels.

Neuroprotective Effect of Methanolic Ajwa Seed Extract on Lipopolysaccharide-Induced Memory Dysfunction and Neuroinflammation: In Vivo, Molecular Docking and Dynamics Studies

“…In order to identify molecular-level interactions, binding mode analysis was performed for those compounds that displayed binding affinity of −7 or above for AChE and −6 or above for COX-2; those binding modes were selected for discussion, which displayed interaction with key residues. The AChE literature search and crystal structure analysis revealed Tyr70, Asp72, Trp84, Gly118, Gly119, Tyr121, Ser200, Ala201, Trp279, Glu337, and His440 [ 27 , 28 , 29 ]. Similarly, for COX-2, the literature search and crystal structure analysis revealed Arg120, Ser530, Tyr355, Tyr385, Ala527, Val349, Leu352, Leu531, and Trp387 [ 30 ].…”

“…For COX-2, Arg120, Ser530, Tyr355, Tyr385, Ala527, Val349, Leu352, Leu531 and Trp387 were considered important for binding mode analysis. In the case of AChE residues, Ser200, Glu337, and His440 form the catalytic triad, while residues Gly118, Gly119, and Alanine together make the oxyanion binding sites [ 27 , 28 ]. The peripheral aromatic binding site is made up of Asp72.…”

Impact of levetiracetam on cognitive impairment, neuroinflammation, oxidative stress, and neuronal apoptosis caused by lipopolysaccharides in rats

“…The rats were allocated to four groups (n = 6) for the experimental procedure. The schedules of the prophylactic drug (LEVE) treatment and induction of neurotoxicity (LPS) were followed according to previous reports with minor modifications ( Kamdi et al, 2021 , Mani et al, 2022a ). The control rats were administered 30 days with the vehicle (NS; 10 mL/kg, p.o.)…”

“…), and neuronal deficits were induced with LPS, similar to the LPS-induced group. The doses of LPS ( Rahim et al, 2021 ) and LEVE ( Mani et al, 2022a ) used in this experiment are based on our previous reports. For the assessment of cognitive performance, EPM procedures were carried out on days 26 (training) and 27 (retention).…”

Nicotinic acetylcholine receptors and learning and memory deficits in Neuroinflammatory diseases

“…A complex combination of genetic factors, life events, and lifestyles triggers these pathological processes. Mental triggers include traumatic events, depression ( Gu et al, 2022 ), physical stressors such as radiotherapy ( Gu et al, 2022 ; Gutierrez-Quintana et al, 2022 ), traumatic brain injury, viral or bacterial infections ( Akinci et al, 2022 ; Francis et al, 2023 ), and exposure to toxins such as toxic heavy metals ( Mani et al, 2022 ; Xu et al, 2022 ), insecticides, chemotherapy agents, medicaments, and a fatty diet. A recent study showed that neuroinflammation could also be associated with epigenetic changes induced by Posttraumatic Stress Disorder (PTSD) ( Wolf et al, 2018 ) (see Figure 1 ).…”