**2.4 Oxidative and nitrosative stress**

Exposure of astrocytes to ammonia, inflammatory cytokines, hyponatremia and benzodiazepines leads to enhanced production of RNS & ROS via the Calcium dependent N-methyl-D-aspartate (NMDA) pathway. RNS and ROS cause tyrosine nitration, leading to altered BBB permeability and astrocyte swelling. (39, 40)

#### **2.5 Manganese theory**

In normal healthy individuals, Maganese is cleared by liver and excreted into the bile. Manganese is known to stimulate the Translocator proteins located on astrocytes, leading to enhanced neurosteroid synthesis. In cirrhotic patients, it accumulates in the basal ganglia because of decreased excretion of Maganese due to portosystemic shunting and promotes formation of Alzheimer's type 2 astrocytes.(41) Brain magnetic resonance imaging (MRI) in cirrhotic patients has shown changes which are due to accumulation of Maganese in basal ganglia particularly in the palladium, putamen and caudate nucleus.(41)
