Background:
Diabetes is a chronic metabolic disorder affecting the central nervous system.
A growing body of evidence has depicted that high glucose level leads to the activation of the
transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting
TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach.
Objective:
The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate
(2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment.
Methods:
Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were
randomly divided into the treatment group, model group and age-matched control and pre se
group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural
treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction
and the hippocampus and cortex were isolated. After that, protein and mRNA expression study
was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex.
Results: :
Our study showed the 10th week diabetic animals developed cognitive impairment, which
was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2
mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex.
However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent
protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP
response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95).
Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF)
were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit
alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment
with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic
rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the
hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic
animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9),
CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and
BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic
animals.
Conclusion: :
This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes-
induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated
downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced
cognitive impairment.
Role of the α-Kinase Domain in Transient Receptor Potential Melastatin 6 Channel and Regulation by Intracellular ATP
