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A High-performance Liquid Chromatography Measurement of Kynurenine and Kynurenic Acid: Relating Biochemistry to Cognition and Sleep in Rats

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Published on: August 19, 2018

Montelukast potentiates the protective effect of rofecoxib against kainic acid-induced cognitive dysfunction in rats

Anil Kumar¹, Atish Prakash, Deeksha Pahwa

¹Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh-160014, India. kumaruips@yahoo.com

Pharmacology, Biochemistry, and Behavior

|August 11, 2012

Abstract:

There is an evolving consensus that mild cognitive impairment (MCI) serves as a prodrome to Alzheimer's disease. Antioxidants and COX-2 (cyclo-oxygenase-2) inhibitors have also been reported to have beneficial effects against conditions of memory impairment. Newer drugs like cysteinyl leukotriene inhibitors have shown neuroprotective effect in animal models of ischemia. Thus, the present study purports to explore the potential role of montelukast (a cysteinyl leukotriene inhibitor) in concert with rofecoxib (COX-2 inhibitor) and caffeic acid (a 5-LOX inhibitor and potent antioxidant) against kainic acid induced cognitive dysfunction in rats. In the experimental protocol, kainic acid (0.4 μg/2 μl) in artificial cerebrospinal fluid (ACSF) was given intrahippocampally (CA3 region) to induce a condition similar to MCI. Memory performance was measured on days 10-14 and the locomotor activity was measured on days 1, 7 and 14. For estimation of biochemical, mitochondrial and histopathological parameters, animals were sacrificed on day 14, stored at -80 °C and the estimation was done on the 15th day. The treatment groups consisting of montelukast (0.5 and 1 mg/kg), rofecoxib (5 and 10 mg/kg) and caffeic acid (5 and 10 mg/kg) showed significant improvement in memory performance, oxidative stress parameters and mitochondrial function as compared to that of control (kainic acid treated), however, combination of montelukast with rofecoxib showed significant improvement in their protective effect. Thus the present study emphasizes the positive modulation of cysteinyl leukotriene receptor inhibition on COX (cyclooxygenase) and LOX (lipoxygenase) pathways in the control of the neuroinflammation in kainic acid induced cognitive dysfunction in rats.

Insights

Montelukast, rofecoxib, and caffeic acid improved memory and reduced oxidative stress in rats with cognitive dysfunction. Combining montelukast and rofecoxib enhanced these protective effects against neuroinflammation.

Area of Science:

Neuroscience
Pharmacology
Biochemistry

Background:

Mild cognitive impairment (MCI) is increasingly recognized as a precursor to Alzheimer's disease.
Antioxidants and cyclo-oxygenase-2 (COX-2) inhibitors show promise in mitigating memory impairment.
Cysteinyl leukotriene inhibitors exhibit neuroprotective properties in animal models.

Purpose of the Study:

To investigate the potential of montelukast (cysteinyl leukotriene inhibitor), rofecoxib (COX-2 inhibitor), and caffeic acid (5-LOX inhibitor/antioxidant) in treating kainic acid-induced cognitive dysfunction in rats.
To evaluate the combined effects of these agents on memory, oxidative stress, and mitochondrial function.
To explore the modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways in neuroinflammation.

Main Methods:

Kainic acid was administered intrahippocampally to induce MCI-like conditions in rats.
Memory performance and locomotor activity were assessed.
Biochemical, mitochondrial, and histopathological parameters were analyzed post-treatment.
Rats were treated with varying doses of montelukast, rofecoxib, and caffeic acid, individually and in combination.

Main Results:

Montelukast, rofecoxib, and caffeic acid significantly improved memory performance and oxidative stress markers compared to controls.
All tested agents demonstrated positive effects on mitochondrial function.
The combination of montelukast and rofecoxib exhibited a synergistic enhancement of protective effects.

Conclusions:

Montelukast, rofecoxib, and caffeic acid show therapeutic potential for cognitive dysfunction and neuroinflammation.
Cysteinyl leukotriene receptor inhibition positively modulates COX and LOX pathways.
Combination therapy, particularly montelukast with rofecoxib, offers enhanced neuroprotection in this model.

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