Andrographolide improves PCP-induced schizophrenia-like behaviors through blocking interaction between NRF2 and KEAP1

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Schizophrenia is a major global psychological illness.
• Inflammation and oxidative stress are implicated in schizophrenia's development.
• Andrographolide exhibits anti-inflammatory and antioxidant properties.

Purpose of the Study:

• To investigate andrographolide's potential to alleviate schizophrenia-like behaviors.
• To determine if andrographolide's effects are mediated by inhibiting inflammation and oxidative stress.
• To explore the role of the NRF-2 pathway in andrographolide's therapeutic action.

Main Methods:

• Utilized a Phencyclidine (PCP)-induced mouse model to mimic schizophrenia.
• Administered andrographolide at doses of 5 mg/kg and 10 mg/kg.
• Assessed behavioral changes, inflammatory markers, oxidative stress levels, and key protein expressions (NRF-2, HO-1, NQO-1, KEAP1).
• Investigated the NRF-2 pathway using an inhibitor (ML385).

Main Results:

• Andrographolide administration improved locomotor activity, forced swimming, and novel object recognition in the mouse model.
• It inhibited PCP-induced inflammatory cytokine production and reduced phosphorylation of key signaling proteins (p-p65, p-IκBα, p-p38, p-ERK1/2).
• Andrographolide decreased oxidative stress markers (MDA, GSH) and increased antioxidant enzyme activity (SOD, CAT, GCH-px).
• It enhanced NRF-2 pathway activation by increasing NRF-2, HO-1, and NQO-1 expression and promoting NRF-2 nuclear translocation.
• Inhibition of NRF-2 abolished andrographolide's beneficial effects.

Conclusions:

• Andrographolide effectively ameliorates schizophrenia-like behaviors in a PCP-induced mouse model.
• Its therapeutic effects are attributed to the inhibition of inflammation and oxidative stress.
• The NRF-2 pathway is crucial for andrographolide's antioxidant and anti-schizophrenia-like actions.