Synergistic Neuroprotective Effects of Atorvastatin and Rosemary Extract in Experimental Neurotoxicity in Rats: Integrated Toxicological, Anatomical, and Histopathological Evaluation

Abstract

Background

Aluminum chloride (AlCl3)-induced neurotoxicity is accompanied by exaggerated oxidative stress, neuroinflammation, mitochondrial damage, neuronal cell death, and incremental loss of memory and cognitive functions. Atorvastatin, in addition to its lipid-lowering action, shows a multitude of pleiotropic anti-inflammatory and antioxidant activities, and rosemary (Rosmarinus officinalis) is a rich source of naturally occurring neuroprotective compounds. Yet, very little is known about the impact of simultaneous use of atorvastatin and rosemary extract in AlCl3‎-induced neurotoxicity.

Objective

This work aims at assessing the efficacy of individual or combinatorial administration of atorvastatin and rosemary extract in ameliorating AlCl3-induced neurotoxicity using behavioral, biochemical, molecular, histopathological and anatomical analysis.

Methods

Seventy adult male Wistar rats were randomly divided into seven experimental groups. One group served as the control group and received distilled water only, whereas the remaining six groups were considered experimental groups. The six experimental groups were orally exposed to AlCl₃ to induce neurotoxicity and were subsequently treated orally with either atorvastatin or rosemary extract alone or with their combination for 6 weeks. The Morris water maze, Y-maze, Open Field, and Rotarod tests were used to assess learning, memory, motor activity, and motor coordination, respectively. Thereafter, oxidative stress markers, inflammatory cytokines, neurotransmitter levels, apoptotic protein expression, antioxidant pathways, and brain histopathological changes were evaluated. The obtained data were analyzed using one-way analysis of variance (ANOVA), followed by an appropriate post hoc test for multiple comparisons

Results:

Aluminum chloride exposure resulted in significant loss of cognitive functions and motor performance along with marked rise in markers of oxidative stress, augmented inflammatory indices, declined endogenous antioxidant capacity, imbalanced levels of neurotransmitters and augmented apoptotic markers in brain tissue accompanied with severe damage of neural tissue (p < 0.001).

Both atorvastatin and rosemary extract were found effective in alleviating AlCl3-induced oxidative stress, neuroinflammation, neurodegeneration, behavioral and motor deficits. In comparison with their individual effects, the combined treatment significantly protected against AlCl3-induced neurotoxicity more effectively and completely. Atorvastatin plus rosemary combination achieved best improvements in all behavioral, biochemical and molecular parameters and reduced the neuronal injury to near normal levels by promoting activation of antioxidant Nrf2/HO-1 signaling, inhibiting inflammatory NF-kB pathway, suppressing apoptotic signals and protecting integrity of neural cells.

Conclusion:

The combined treatment of atorvastatin and rosemary extract showed a superior neuroprotective potential against aluminum chloride induced neurotoxicity as compared to the treatment with either drug alone. This enhanced synergistic effect may stem from their combined beneficial actions on oxidative stress, inflammatory response, apoptosis and antioxidant mechanisms that contribute to protection from oxidative stress-induced neural injury.