Antidepressant and Neuroprotective Effects of 3-Hydroxy Paroxetine, an Analog of Paroxetine in Rats

Abstract

Background Paroxetine (PX), is a widely used antidepressant with side effects such as weakness, dizziness and trouble sleeping. In search of novel compounds with better efficacy and less side effect, we synthesized 3HPX, a hydroxylated analog of PX, and compared the two in-silico for their pharmacokinetic and binding properties and in-vivo for their antidepressant and potential neuroprotective effects. Methods In-silico studies compared pharmacological properties as well as interactions of PX and 3HPX with the serotonin transporter. In-vivo studies utilized an animal model of comorbid depression-Parkinson’s disease (PD). Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide (LPS) in the striatum (unilaterally), followed by 14 days of once daily injection (i.p.) of 10 mg/kg of PX or 3HPX. Animals were tested for motor asymmetry and locomotor activity as well as indices of anhedonia and helplessness, using sucrose preference and forced swim tests, respectively. Brains of these animals were collected after the last test and tyrosine hydroxylase (TH) positive neurons in substantia nigra pars compacta (SNpc) and Iba-1 positive stained microglia in ipsilateral striatum were measured. Results In-silico findings indicated that 3HPX could bind stronger to serotonin transporter and also have a better clearance and hence less toxicity compared to PX. In-vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in TH + cells in SNpc, and more ramified Iba-1 + cells by 3HPX compared to PX. Conclusion The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared to PX and hence potential utility in PD-depression co-morbidity.