# Crocin Mitigates Glutamate Excitotoxicity and Tau Hyperphosphorylation by Modulating EAAT2 and Akt/Tau Pathway in a Scopolamine-induced Rat Model of Alzheimer’s Disease

## TL;DR

Crocin, a compound from saffron, helps protect brain cells in a rat model of Alzheimer's by reducing harmful glutamate levels and improving key brain signaling pathways.

## Contribution

This study demonstrates that crocin mitigates glutamate excitotoxicity and tau hyperphosphorylation by modulating EAAT2 and Akt/Tau pathways in an Alzheimer’s rat model.

## Key findings

- Crocin treatment reduced glutamate levels and restored EAAT2 activity in scopolamine-induced Alzheimer’s rats.
- Crocin increased p-Akt expression and reduced tau phosphorylation, indicating neuroprotective effects.
- Histological analysis showed structural recovery of hippocampal neurons following crocin treatment.

## Abstract

Alzheimer’s disease (AD) is characterized by glutamatergic dysregulation and excitotoxicity, largely associated with impaired activity of the excitatory amino acid transporter 2 (EAAT2). Downregulation of EAAT2 results in glutamate accumulation, N-Methyl-D-Aspartate (NMDA) receptor overactivation, and neuronal injury. Crocin (Cr), a carotenoid compound extracted from saffron (Crocus sativus), exhibits potent antioxidant and neuroprotective properties, particularly in experimental models of neurodegeneration. Forty-eight adult male rats were divided into six groups: control (saline), crocin (50 mg/kg), scopolamine (3 mg/kg for 7 days), scopolamine followed by memantine (M) (20 mg/kg), scopolamine followed by crocin, and scopolamine followed by both memantine and crocin. This study aimed to evaluate the therapeutic potential of crocin, alone and in combination with memantine, in a scopolamine-induced rat model of Alzheimer’s disease, with a focus on EAAT2 modulation. Scopolamine administration significantly elevated glutamate, NMDAR and p-tau levels while reducing p-Akt, GABA and EAAT2 levels, accompanied by marked hippocampal neurodegeneration. In contrast, crocin treatment, either alone or in combination with memantine, restored neurotransmitter balance, downregulated NMDAR, upregulated EAAT2, increased p-Akt expression level and reduced tau phosphorylation. Histological analysis further confirmed notable structural recovery of hippocampal neurons.

The online version contains supplementary material available at 10.1007/s11064-026-04692-z.