EFFECT OF DROTAVERINE, A PHOSPHODIESTERASE 4 INHIBITOR IN SCOPOLAMINE-INDUCED COGNITIVE IMPAIRMENT IN RATS
Objective: Cognitive impairment (CI) is a progressive neurodegenerative disorder and causes significant dementia in the elderly. Intracellular cyclic AMP (cAMP) signaling has been well established in the mediation of memory. Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cAMP and/or cyclic GMP. Drotaverine is a novel non-anticholinergic smooth muscle antispasmodic which acts by inhibiting PDE-4. It is now clinically used in smooth muscle spasms (intestinal, biliary and renal colic, irritable bowel syndrome, uterine spasms, etc.) without anticholinergic side effects. Since Drotaverine has PDE4 inhibition property, its role in learning and memory was evaluated in this study and found that it has memory enhancing effect comparable with donepezil in scopolamine-induced CI in rats.
Methods: Learning and memory were assessed with two behavioral models, namely, elevated plus maze (EPM) and Y maze. CI was produced by scopolamine. Rats were divided into five groups, Group I treated with normal saline, Group II treated with scopolamine, and Groups III, IV, and V were treated with donepezil, Drotaverine, and both, respectively.
Results: The result analysis revealed significant differences in transfer latency in EPM performance between Groups III, IV, V and Group II (***p<0.001). The results of spontaneous alternation in Y maze show that there was a significant difference among all the treatments groups (p<0.001).
Conclusion: Drotaverine has promising memory enhancing effect in CI induced by scopolamine in rats. Further clinical trials are needed to prove this finding which has been elicited in animal models.
2. Suh YH, Checler F. Amyloid precursor protein, presenilin, and alpha-synuclein: Molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev 2002;54:469-525.
3. Ortega-Martínez S. A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front Mol Neurosci 2015;8:46.
4. Sapio L, di Maiolo F, Illiano M, Esposito A, Chiosi E, Spina A, et al. Targeting protein kinase A in cancer therapy: An update. EXCLI J 2014;13:843-55.
5. Rutten K, Basile JL, Prickaerts J, Blokland A, Vivian JA. Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques. Psychopharmacology (Berl) 2008;196:643-8.
6. Rutten K, Prickaerts J, Blokland A. Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action. Neurobiol Learn Mem 2006;85:132-8.
7. Zhang HT, O’Donnell JM. Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats. Psychopharmacology (Berl) 2000;150:311-6.
8. Bolaji OO, Onyeji CO, Ogundaini AO, Olugbade TA, Ogunbona FA. Pharmacokinetics and bioavailability of drotaverine in humans. Eur J Drug Metab Pharmacokinet 1996;21:217-21.
9. Klinkenberg I, Blokland A. The validity of scopolamine as a pharmacological model for cognitive impairment: A review of animal behavioral studies. Neurosci Biobehav Rev 2010;34:1307-50.
10. Tiseo PJ, Perdomo CA, Friedhoff LT. Metabolism and elimination of 14C-donepezil in healthy volunteers: A single-dose study. Br J Clin Pharmacol 1998;46:19-24.
11. Pattanashetti LA, Taranalli AD, Parvatrao V, Malabade RH, Kumar D. Evaluation of neuroprotective effect of quercetin with donepezil in scopolamine-induced amnesia in rats. Indian J Pharmacol 2017;49:60-4.
12. Shin JW, Seol IC, Son CG. Interpretation of animal dose and human equivalent dose for drug development. J Korean Orient Med 2010;31:1-7.
13. Nigam A, Kulshreshtha M, Panjwani D. Pharmacological evaluation of Hibiscus abelmoschus against scopolamine-induced amnesia and cognitive impairment in mice. Adv Hum Biol 2019;9:116-23.
14. Kamila S, Madhav NV, Sarkar CN. Safety and efficacy study of herbal polyphyto formulations: For its learning and memory enhancing properties. Int J Pharm Pharm Sci 2016;8:119-23.
15. Zaki HF, Abd-El-Fattah MA, Attia AS. Naringenin protects against scopolamine-induced dementia in rats. Bull Fac Pharm 2014;52:15-25.
16. Benatoui R, Bairi A, Tahraoui A. Estimation of the anxiolytic-like effect of the ?-carboline alkaloid harmine on stressed pregnant rats. Int J Pharm Pharm Sci 2017;9:166-72.
17. Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J. Selective phosphodiesterase inhibitors: A promising target for cognition enhancement. Psychopharmacology (Berl) 2009;202:419-43.
18. Blokland A, Menniti FS, Prickaerts J. PDE inhibition and cognition enhancement. Expert Opin Ther Pat 2012;22:349-54.
19. Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: Molecular mechanisms and physiological functions. Physiol Rev 2011;91:651-90.
20. Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, et al. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology 2004;47:1081-92.
21. van der Staay FJ, Rutten K, Barfacker L, Devry J, Erb C, Heckroth H, et al. The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology 2008;55:908-18.
22. Jin F, Gong QH, Xu YS, Wang LN, Jin H, Li F, et al. Icariin, a phosphodiesterase-5 inhibitor, improves learning and memory in APP/ PS1 transgenic mice by stimulation of NO/cGMP signalling. Int J Neuropsychopharmacol 2014;17:871-81.
23. Wang H, Peng MS, Chen Y, Geng J, Robinson H, Houslay MD, et al. Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors. Biochem J 2007;408:193-201.
24. Gong B, Shelanski M, Arancio O. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest 2004;114:1624-34.
25. Vanmierlo T, Creemers P, Akkerman S, van duinen M, Sambeth A, de Vry J, et al. The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses. Behav Brain Res 2016;303:26-33.
26. Bruno O, Fedele E, Prickaerts J, Parker LA, Canepa E, Brullo C, et al. GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses. Br J Pharmacol 2011;164:2054-63.
27. Lieben CK, Blokland A, Sik A, Sung E, van Nieuwenhuizen P, Schreiber R. The selective 5-HT6 receptor antagonist Ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat. Neuropsychopharmacology 2005;30:2169-79.
This work is licensed under a Creative Commons Attribution 4.0 International License.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.