Oral administration of coenzyme Q10 ameliorates memory impairment induced by nicotine-ethanol abstinence through restoration of biochemical changes in male rat hippocampal tissues

Abstract

Substance abuse among adolescents has become a growing issue throughout the world. The significance of research on this life period is based on the occurrence of neurobiological changes in adolescent brain which makes the individual more susceptible for risk-taking and impulsive behaviors. Alcohol and nicotine are among the most available drugs of abuse in adolescents. Prolonged consumption of nicotine and alcohol leads to drug dependence and withdrawal which induce various dysfunctions such as memory loss. Coenzyme Q10 (CoQ₁₀₎ is known to improve learning and memory deficits induced by various pathological conditions such as Diabetes mellitus and Alzheimer's disease. In the present study we investigated whether CoQ₁₀ treatment ameliorates memory loss following a nicotine-ethanol abstinence. Morris water maze and novel object recognition tests were done in male Wistar rats undergone nicotine-ethanol abstinence and the effect of CoQ10 was assessed on at behavioral and biochemical levels. Results indicated that nicotine-ethanol abstinence induces memory dysfunction which is associated with increased oxidative and inflammatory response, reduced cholinergic and neurotrophic function plus elevated Amyloid-B levels in hippocampi. CoQ₁₀ treatment prevented memory deficits and biochemical alterations. Interestingly, this ameliorative effect of CoQ₁₀ was found to be dose-dependent in most experiments and almost equipotential to that of bupropion and naloxone co-administration. CoQ₁₀ treatment could effectively improve memory defects induced by nicotine-ethanol consumption through attenuation of oxidative damage, inflammation, amyloid-B level and enhancement of cholinergic and neurotrophic drive. Further studies are required to assess the unknown side effects and high dose tolerability of the drug in human subjects.

Keywords: Abstinence; Adolescence; Coenzyme Q10; Ethanol; Memory; Nicotine.

Figure 1

Ethanol drinking profile and blood ethanol levels. (A) Ethanol drinking amount (ml) was gradually increased during the entire experimental protocol in all groups (only 7 time points are shown within PNDs 21–42) and this caused a dramatic increase in blood ethanol levels (mg/dl) of all animals received ethanol in their drinking water, compared to the control group (p < 0.0001). Abbreviations: Nic: nicotine, Eth: ethanol, CoQ10: Coenzyme Q10, Bup: bupropion, Nal: naloxone, P*** < 0.001 vs. Vehicle.

Figure 2

Assessment of memory by MWM test. Nic-Eth abstinence impaired the development of spatial memory in rats. This is characterized by reduced slope of the curve in Nic-Eth vs. Vehicle group. CoQ₁₀ treatment, dose dependently reversed the mentioned effects of Nic-Eth abstinence (A). Nic-Eth group displayed reduced time of swimming in the target quadrant vs. the control subjects and this effect was reversed by CoQ₁₀ treatment at the dose 400mg/kg. Furthermore, bupropion-naloxone combination (Nic-Eth-Bup-Nal group) could effectively reverse the effect of Nic-Eth abstinence almost with a potency equal to that of CoQ10 400 mg/kg. Administration of CoQ₁₀ 400 mg/kg in naïve rats caused the most potent ameliorative effect in all experimental groups (B). Abbreviations: Nic: nicotine, Eth: ethanol, CoQ10: Coenzyme Q10, Bup: bupropion, Nal: naloxone and MWM: Morris water maze. P*** < 0.001 vs. Vehicle, P +  +  < 0.01 and P +  +  +  < 0.001 vs. Nic-Eth. P**** < 0.0001.

Figure 3

Assessment of memory by NOR test. Total exploration time was not different among the experimental groups (A). Animals undergone Nic-Eth abstinence, displayed impaired memory function compared to the control (vehicle) group. This was characterized by reduction in the time animal spent to explore the novel object (B) and the reduced discrimination index (C). As shown, this adverse effect was dose dependently reversed by CoQ₁₀ treatment (B and C). Abbreviations: Nic: nicotine, Eth: ethanol, CoQ10: Coenzyme Q10, Bup: bupropion, Nal: naloxone and NORT: novel object recognition test. P** < 0.01 and P**** < 0.0001.

Figure 4

Assessment of oxidative profile in hippocampal tissues. In nicotine-ethanol withdrawn rats, concentrations of pro-oxidant markers including MDA and nitrite was increased and this effect was reversed by CoQ10 treatment (A and E). On the contrary, anti-oxidant indices including thiol level and SOD/CAT activity were elevated in hippocampi and again this effect was prevented by CoQ10 administration (B, C and D). It should be noted that for all markers, the effect of CoQ10 at its highest dose (400 mg/kg) was almost equipotential to that of the Bup + Nal and the most potent effect was observed in naïve rats received CoQ10 alone (A–D). Abbreviations: Nic: nicotine, Eth: ethanol, CoQ10: Coenzyme Q10, Bup: bupropion, Nal: naloxone, MDA: malondialdehyde, SOD: superoxide dismutas. P**** < 0.0001.

Figure 5

Assessment of inflammatory profile in hippocampal tissues. In nicotine-ethanol withdrawn rats, concentrations of anti- and pro-inflammatory cytokines were decreased and increased including IL-10 and TNF-α, respectively (A and B). As shown, for both indices, CoQ10 treatment effectively prevented the mentioned effect. In addition, the effect of CoQ10 at the dose of (400 mg/kg) was almost equipotential to that of the Bup + Nal and the most potent effect was found in naïve rats treated by CoQ10 alone. Abbreviations: Nic: nicotine, Eth: ethanol, CoQ10: Coenzyme Q10, Bup: bupropion, Nal: naloxone, IL-10: Interleukin-10 and TNF-α: tumor necrosis factor-alpha. P**** < 0.0001.

Figure 6

Assessment of AChE, BDNF and amyloid-B in hippocampal tissues. In nicotine-ethanol withdrawn rats, the enzymatic activity of AChE as well as the concentration of amyloid-B was elevated in hippocampal tissues (A and C), however, BDNF level was diminished significantly (B). In all markers, the effect of CoQ10 at the dose of (400 mg/kg) was almost equipotential to that of the Bup + Nal and the most potent effect was found in naïve rats treated by CoQ10 alone. Abbreviations: Nic: nicotine, Eth: ethanol, CoQ10: Coenzyme Q10, Bup: bupropion, Nal: naloxone, AChE: acetylcholinesterase and BDNF: brain-derived neurotrophic factor. P** < 0.01 and P**** < 0.0001.