Background and purpose - In spite of decades research the etiology of Parkinson’s disease (PD) is not yet well defined. The present study was conducted to assess the role of eukaryotic initiation factor 2 (eIF2α) in progressive dopaminergic neuronal death. Experimental approach - The investigation was done employing experimental rat model of parkinsonism and utilizing various interventions (YM08, 4µ8C, AEBSF, salubrinal, ursolic acid) of endoplasmic reticulum (ER) stress signaling. The mRNA and protein level of ER stress related signaling factors (GRP78, IRE1α, ATF6, eIF2α, ATF4, XBP-1, GADD153) were estimated along with various biochemical alterations (reactive oxygen species generation, levels of nitrite level, intracellular calcium, mitochondrial membrane potential), neuronal morphology and neuronal apoptosis after 3 and 7 day of experiment initiation. Key results - Findings with single administration of interventions showed that salubrinal exhibited significant protection against rotenone induced alterations in ER stress related signaling factors in comparison to other interventions. Therefore, further study was expanded with repeat dose of salubrinal. Rotenone administration in rat brain caused the dose dependent progressive neuronal death which was significantly attenuated with salubrinal treatment involving its diverse effects on altered levels of various ER stress related signaling factors and altered biochemical parameters. Conclusion and implications - Findings showed that rotenone administration induced PD pathology involve the dose dependent progressive neuronal death including various biochemical alterations with critical role of eukaryotic initiation factor 2α, suggesting the potential pharmacological utilization of salubrinal or salubrinal like molecule in therapeutics of Parkinson’s diseases.