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Tramadol ameliorates behavioural, biochemical, mitochondrial and histological alterations in ICV-STZ-induced sporadic dementia of Alzheimer’s type in rats

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Abstract

Alzheimer disease represents a major public health issue with limited therapeutic interventions. We explored the possibility of therapeutic approach by repurposing of tramadol in a sporadic animal model of Alzheimer’s type. Streptozocin (STZ 3 mg/kg; bilaterally) was injected to male SD rats through intracerebroventricular (ICV) route. Drug treatment was started just after streptozocin administration and continued for 3 weeks. The rats were killed on the 21st day following the last behavioral test, and cytoplasmic fractions of the hippocampus and pre-frontal cortex were prepared for the quantification of acetylcholinesterase, oxidative stress parameter, mitochondrial enzymes activity and histological examination. Tramadol (5, 10 and 20 mg/kg, i.p.) was used as a treatment drug, and memantine (10 mg/kg, i.p.) was used as a standard. Tramadol significantly attenuated behavioral, biochemical, mitochondrial and histological alterations at low (5 mg/kg) and intermediate (10 mg/kg) dose, suggesting its neuroprotective potential in ICV-STZ-treated rats. Further, the neuroprotective effect of tramadol (10 mg/kg) was comparable to memantine (10 mg/kg). In conclusion, our results indicate the effectiveness of tramadol in preventing ICV-STZ-induced cognitive impairment as well as mito-oxidative stress. Further, these findings reveal the possibility of MOR agonist as a therapeutic approach for sporadic Alzheimer disease.

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Abbreviations

AChE:

Acetylcholinesterase

ANOVA:

Analysis of variance

BBB:

Blood brain barrier

BSA:

Bovine serum albumin

CA-1:

Cornus Ammonis-1

DTNB:

5,5′-Dithio-bis-[2-nitrobenzoic acid

EGTA:

Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid

GABA-A:

Gamma-aminobutyric acid-A

GSH:

Reduced glutathione

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

i.p.:

Intraperitoneal

ICV-STZ:

Intracerebroventricular-streptozocin

MORs:

Mu-opioid receptors

MDA:

Malondialdehyde

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NAD+:

Nicotinamide adenine dinucleotide

NMDA:

N-Methyl-d-aspartate

NO:

Nitric oxide

NOS:

Nitric oxide synthase

ROS:

Reactive oxygen species

sAD:

Sporadic Alzheimer disease

SDH:

Succinate dehydrogenase

SOD:

Superoxide dismutase

TBARS:

Thiobarbituric acid reactive substance

TSTQ:

Time spent in target quadrant

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Acknowledgements

Authors would like to thank the financial support of Council of Scientific and Industrial Research (09/135/705/2014- EMR-I), New Delhi, India, for carrying out this work.

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  1. Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, 160014, India

    Dinesh K. Dhull & Anil Kumar

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Correspondence to Anil Kumar.

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Dhull, D.K., Kumar, A. Tramadol ameliorates behavioural, biochemical, mitochondrial and histological alterations in ICV-STZ-induced sporadic dementia of Alzheimer’s type in rats. Inflammopharmacol 26, 925–938 (2018). https://doi.org/10.1007/s10787-017-0431-3

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