# Indole-3-Carbinol and Its Derivatives as Neuroprotective Modulators

## TL;DR

This paper reviews how indole-3-carbinol and its derivatives may protect neurons by activating brain signaling pathways linked to neuroprotection and antioxidants.

## Contribution

The paper highlights the novel therapeutic potential of indole-3-carbinol derivatives in neurodegenerative diseases through dual activation of TrkB and Nrf2 pathways.

## Key findings

- Indole-3-carbinol and its derivatives mimic BDNF activity to activate TrkB signaling.
- These compounds activate Nrf2 by disrupting the Nrf2-Keap1 complex, enhancing antioxidant defenses.
- Combined activation of TrkB and Nrf2 pathways offers a promising strategy for neuroprotection.

## Abstract

Brain-derived neurotrophic factor (BDNF) and its downstream tropomyosin receptor kinase B (TrkB) signaling pathway play pivotal roles in the resilience and action of antidepressant drugs, making them prominent targets in psychiatric research. Oxidative stress (OS) contributes to various neurological disorders, including neurodegenerative diseases, stroke, and mental illnesses, and exacerbates the aging process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant responsive element (ARE) serves as the primary cellular defense mechanism against OS-induced brain damage. Thus, Nrf2 activation may confer endogenous neuroprotection against OS-related cellular damage; notably, the TrkB/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, stimulated by BDNF-dependent TrkB signaling, activates Nrf2 and promotes its nuclear translocation. However, insufficient neurotrophin support often leads to the downregulation of the TrkB signaling pathway in brain diseases. Thus, targeting TrkB activation and the Nrf2-ARE system is a promising therapeutic strategy for treating neurodegenerative diseases. Phytochemicals, including indole-3-carbinol (I3C) and its metabolite, diindolylmethane (DIM), exhibit neuroprotective effects through BDNF’s mimetic activity; Akt phosphorylation is induced, and the antioxidant defense mechanism is activated by blocking the Nrf2-kelch-like ECH-associated protein 1 (Keap1) complex. This review emphasizes the therapeutic potential of I3C and its derivatives for concurrently activating neuronal defense mechanisms in the treatment of neurodegenerative diseases.