Pyrroloquinoline quinine prevents aluminum-induced cognitive deficit in rats

P158 P1-013

Sunday, July 14, 2013: Poster Presentations: P1 PIPERINE ENHANCES THE NEUROPROTECTIVE EFFECTS OF CURCUMIN AGAINST MILD TRAUMATIC BRAIN INJURY–INDUCED COGNITIVE DEFICITS: BEHAVIORAL, BIOCHEMICAL, MITOCHONDRIAL AND MOLECULAR CORRELATES

Puneet Rinwa1, Anil Kumar2, 1University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India; 2Panjab University, Chandigarh, India. Contact e-mail: [email protected] Background: Cognitive dysfunction following mild traumatic brain injury (MTBI) is a common clinical observation, but the therapeutic strategies underlying this loss of function has not been well-characterized. Curcumin, a major active component isolated from Curcuma longa is currently being investigated in different neurological problems including cognitive loss. Dietary phytochemicals are now days used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study was designed to elucidate the neuroprotective mechanism of curcumin and its co-administration with piperine against mild traumatic brain injury (MTBI) induced cognitive deficits in rats. Methods: Wistar rats undergone MTBI were analyzed after post-surgical rehabilitation period of 2 weeks. Animals were then treated with different doses of curcumin (100, 200 and 400 mg/kg; p.o.), piperine (20 mg/kg; p.o.) and their combination daily for another 2 weeks. Various behavioral tests (Morris water maze, anhedonic like response in sucrose consumption test) along with setimation of acetlycholinestrase (AChE), serum corticosterone activity, followed by biochemical, mitochondrial and molecular analysis were done Results: MTBI significantly impaired memory performance (delayed latency time in Morris water maze test) and showed a marked decrease in sucrose preference. Further, there was a significant alteration in mitochondrial enzyme complex activities along with increased oxidative stress (elevated malondialdehyde, nitrite concentration and decreased catalase, superoxide dismutase and reduced glutathione levels). Chronic stress also significantly raised acetylcholinesterase and serum corticosterone levels. In addition, MTBI caused a significant increase in levels of inflammatory cytokines (TNF-a), apoptotic factor (caspase-3), and attenuated the amount of neurogenesis factor (BDNF). Treatment with curcumin significantly restored all these behavioral, biochemical, mitochondrial and molecular changes as well as attenuated increased brain acetylcholinesterase and serum corticosterone levels. Further, co-administration of piperine with curcumin significantly potentiated the neuroprotective effects as compared to their effects alone Conclusions: The present study highlights that piperine potentiates the neuroprotective effects of curcumin against cognitive dysfunction induced by mild traumatic brain injury possibly by modulating oxidative-nitrosative stress induced neuroinflammation and apoptosis. P1-014

PYRROLOQUINOLINE QUININE PREVENTS ALUMINUM-INDUCED COGNITIVE DEFICIT IN RATS 1

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Xingqin Zhou , Jiankang Zhang , Yan Shi , Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear, Wuxi, China; 2Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China; 3Materials Chemistry Laboratory, Nanjing University of Science and Technology, Nanjing, China. Contact e-mail: [email protected] Background: Pyrroloquinoline quinine (PQQ), an essential nutrient, antioxidant, has been reported to be promised in the treatment of neurological and psychical disorders. Aluminum, a well-known neurotoxin, has been suggested to be a contributing factor in Alzheimer’s disease. In this study we investigated the possible effect of PQQ on aluminum-induced cognitive impairment in rats. Methods: Rats were exposed to aluminum chloride (100 mg/kg/day) and PQQ (0.2, 2 and 20 mg/kg/day) for 60 days. Cognitive functions and behaviour were evaluated using Morris water maze, swimming and passive avoidance tests. The locomotor functions in animals were assessed using the open field test. Motor coordination was assessed by the

rota-rod test. Moreover, amino acid-like neurotransmitters including Glu, Gly, GABA and Asp in the plasma were determined by HPLC using o-phthalaldehyde as derivatization reagent. Results: Results showed that 2mg/kg PQQ was found to cause significant enhancement of memory in the aluminum-exposed rats. Plasma indicated that the levels of Asp and Glu in the plasma of AD model were significantly higher than those in control group. Conclusions: This study showed that PQQ could prevent the cognitive deficit of aluminum-induced if used in appropriate doses, but the possible pharmacological and molecular mechanisms should be further explored. P1-015

INFLUENCE OF CHRONIC PAIN AND STRESS ON COGNITIVE FUNCTION: 5-HT6 ANTAGONIST IMPROVES THE BEHAVIORAL OUTCOME IN RATS

Ramakrishna Nirogi1, Pradeep Jayarajan2, Venkatesh Goura3, Medapati Rajesh Babu4, Renny Abraham2, Anil Shinde1, 1Suven Life Sciences Ltd, Hyderabad, India; 2Suven Life Sciences, Hyderabad, India; 3 Suven Life Sciences Ltd, Hyderabad, India; 4Suven Life sciences Ltd, Hyderabad, India. Contact e-mail: [email protected] Background: Cognitive function is impaired during chronic pain and stressed states. This impairment strongly affects daily functioning and overall quality of life. This area is still an under-researched area. Thus improving the cognitive function in these states may play a crucial role in the in the management of pain and minimizes passivity, dependency and disability. 5-HT 6 receptors are of special interest, because blockade of 5-HT 6 receptors consistently enhances mnemonic performance in rodents by promoting the release of acetylcholine, glutamate and monoamines in brain regions involved in learning and memory. Methods: The cognitive function i.e. episodic and working memory of animals under chronic pain was evaluated using object recognition task and T- maze task. The effect of stress on cognitive function was also evaluated using object recognition task and radial arm maze task. The effect of 5-HT 6 antagonist treatment on the impaired cognitive function was also evaluated. Results: Chronic pain and stress compromised the episodic memory and working memory of rats. 5-HT 6 antagonist reversed the cognitive impairments observed during chronic pain and stress. Conclusions: 5-HT 6 antagonist could be a potential therapeutic utility for the management of cognitive deficits observed in chronic pain and stressed states. P1-016

RESCUE OF MK-801–INDUCED LEARNING DEFICITS IN AN INCREMENTAL REPEATED ACQUISITION TASK USING AN a5 GABA(A) INVERSE AGONIST

Carolyn Rudy, Holly Hunsberger, Miranda Reed, West Virginia University, Morgantown, West Virginia, United States. Contact e-mail: Miranda. [email protected] Background: NMDA receptors (NMDAR) play a key role in excitatory neurotransmission, synaptic plasticity, learning, and memory, but in Alzheimer’s disease, there is a reduction in synaptic expression of NMDARs. Application of NMDAR agonists to pharmacologically enhance activity of the remaining synaptic NMDARs has proven difficult due to risks of excitotoxicity from calcium influx. An alternative method for increasing the excitatory input of glutamatergic neurons incorporates the use of pharmacological agents (e.g., inverse agonists) that decrease gamma-amino butyric acid (GABA) activity. The a 5 GABA A receptor subtype (a 5 GABA A) is predominantly expressed in the hippocampus and is situated at the base of spines that receive glutamatergic input via NMDA receptors, making it strategically located to modulate NMDARs and well suited as a target for cognitive enhancement. Methods: Here, we attempted to recreate the NMDAR deficits observed in Alzheimer’s disease using MK-801, a high affinity non-competitive NMDAR antagonist, to determine whether inhibition of a 5 GABA A receptors would rescue NMDA-mediated memory deficits. To test this hypothesis, we used an incremental repeated acquisition (IRA) memory test, which is hippocampal- and NMDA-dependent and allowed for longitudinal assessment of drug effects. We first