Antidepressant and Neuroprotective Effects of 3-Hydroxy Paroxetine, an Analog of Paroxetine in Rats.
Rats
Male
Animals
Paroxetine
/ pharmacology
Parkinson Disease
/ drug therapy
Neuroprotective Agents
/ pharmacology
Rats, Wistar
Substantia Nigra
/ metabolism
Tyrosine 3-Monooxygenase
/ metabolism
Serotonin Plasma Membrane Transport Proteins
/ metabolism
Antidepressive Agents
/ pharmacology
Disease Models, Animal
Parkinson’s disease
Paroxetine
depression
lipopolysaccharide
motor activity
neuroinflammation
Journal
The international journal of neuropsychopharmacology
ISSN: 1469-5111
Titre abrégé: Int J Neuropsychopharmacol
Pays: England
ID NLM: 9815893
Informations de publication
Date de publication:
22 03 2023
22 03 2023
Historique:
received:
06
09
2022
accepted:
21
11
2022
pubmed:
27
11
2022
medline:
25
3
2023
entrez:
26
11
2022
Statut:
ppublish
Résumé
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 fewer side effects, we synthesized 3HPX, a hydroxylated analog of PX, and compared the 2 in silico for their pharmacokinetic and binding properties and in vivo for their antidepressant and potential neuroprotective effects. 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 disease. Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide in the striatum (unilaterally), followed by 14 days of once-daily injections (i.p.) of 10 mg/kg 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-positive neurons in substantia nigra pars compacta and Iba-1-positive stained microglia in ipsilateral striatum were measured. In silico findings indicated that 3HPX could bind stronger to serotonin transporter and also have a better clearance and hence less toxicity compared with PX. In vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta, and more ramified Iba-1+ cells by 3HPX compared with PX. The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared with PX and hence potential utility in Parkinson disease depression co-morbidity.
Sections du résumé
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 fewer side effects, we synthesized 3HPX, a hydroxylated analog of PX, and compared the 2 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 disease. Adult male Wistar rats were injected (sterotaxically) with lipopolysaccharide in the striatum (unilaterally), followed by 14 days of once-daily injections (i.p.) of 10 mg/kg 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-positive neurons in substantia nigra pars compacta 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 with PX. In vivo results revealed a more effective reversal of immobility in the swim test, substantial increase in tyrosine hydroxylase-positive cells in the substantia nigra pars compacta, and more ramified Iba-1+ cells by 3HPX compared with PX.
CONCLUSION
The findings suggest superior effectiveness of 3HPX as an antidepressant and neuroprotectant compared with PX and hence potential utility in Parkinson disease depression co-morbidity.
Identifiants
pubmed: 36433759
pii: 6847545
doi: 10.1093/ijnp/pyac077
pmc: PMC10032298
doi:
Substances chimiques
Paroxetine
41VRH5220H
Neuroprotective Agents
0
Tyrosine 3-Monooxygenase
EC 1.14.16.2
Serotonin Plasma Membrane Transport Proteins
0
Antidepressive Agents
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
230-239Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.
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