Acetyl-L-carnitine protective role in gemcitabine-induced neurotoxicity in an experimental rat model

The acetyl ester of L-carnitine (ALC) is essential for cellular energy homeostasis and intermediate metabolism. It demonstrates several well-established biological characteristics, such as antioxidant activity, intracellular membrane stability, mitochondrial function improvement, and neuroprotective and neurotrophic effects. Given that oxidative stress, mitochondrial malfunction, and neuronal membrane damage have been linked to gemcitabine-induced neurotoxicity, ALC may have a preventive role against these negative consequences. Its capacity to boost mitochondrial metabolism and act as an antioxidant points to a potential mechanism for reducing damage to the central nervous system (CNS) caused by gemcitabine. Thus, using an experimental model of gemcitabine-induced neurotoxicity, we explored the possible neuroprotective benefits of ALC.

This study aimed to examine the neuroprotective effects of two distinct dosages of ALC on cognitive impairment in male rats caused by gemcitabine injection. Cognitive function was assessed using well-known behavioral tests, such as the Morris water maze or novel object identification, to offer objective measures of learning and memory. This study aimed to elucidate the possible function of ALC in reducing gemcitabine-related CNS toxicity by evaluating behavioral performance in addition to biochemical indicators of oxidative stress and neuronal damage. It is anticipated that the results of this study will shed light on the dose-dependent effectiveness of ALC in maintaining cognitive function after chemotherapy.

The experiment was conducted using 24 adult male rats, which were randomly assigned to four equal groups (n = 6 per group). Treatments were administered once daily for 28 consecutive days. Group 1 (G1-Control): Rats received a subcutaneous injection of normal saline and served as the negative control. Group 2 (G2-Gemcitabine 25 mg/kg): Rats received 25 mg/kg of Gemcitabine intraperitoneally once daily. Group 3 (G3- ALC 50 mg/kg): Rats received 50 mg/kg of ALC intraperitoneally once daily. Group 4 (G4-Gemcitabine + ALC): Rats received a combination of Gemcitabine (25 mg/kg bw) and ALC (50 mg/kg bw), both administered intraperitoneally once daily. All treatments were administered at the same time each day to ensure consistency, and the animals were monitored throughout the study period to assess their health status and minimize stress.

Rats receiving ALC in addition to gemcitabine demonstrated a significant reduction in gemcitabine-induced adverse effects (p < 0.05) compared with the group treated with gemcitabine alone. This protective effect was mainly seen in characteristics associated with the function of the central nervous system, that ALC plays a neuroprotective role.

The fourth experimental group (G4) had considerably lower levels of β-amyloid and acetylcholinesterase activity than the second (G2) and third (G3) groups. Furthermore, brain sections from the G4 group showed significantly fewer β-amyloid plaques than those from the G2 and G3 groups, according to Congo red staining histological analysis.