N-methyl-d-aspartate by Memantine

Memantine represents a new class of therapeutic agent with efficacy for the symptomatic treatment of moderately severe to severe Alzheimer’s disease (AD) with moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage-dependency and fast kinetics. Treatment with high therapeutic dose of memantine 10 mg/kg obviously reduced the cisplatin-induced neurobehavioral toxicity. Memantine blocks the NMDA receptor pore; the mechanisms whereby NMDA antagonists could be beneficial to neurobehavioral protection [19]. One of the serious unwanted effects of the cisplatin anticancer drug is its neurotoxicity, which can be evoked by the activation of extracellular pathway of apoptosis in cells. Since memantine, a clinically used N-methyl-D-aspartic acid (NMDA) receptor antagonist, shows antiapoptotic action in several models of neuronal cell damage, in this study we evaluated the effect of memantine on the neurobehavioral effect induced by cisplatin in mice[20].In a well-described rodent model, cisplatin exposure at 5–10 mg/kg/d produced several neurological deficits, including hind-limb foot splay, decreased fore- and hind-limb grip strength, ataxia, and skeletal muscle weakness.

Moreover, chemotherapeutic agent exposure resulted in the central–peripheral neuropathy in humans and in laboratory animals, including rats and monkeys. Treatment with memantine significantly improved the neurological deficits; this result was in accordance with [14] who reported that memantine significantly alleviated the cisplatin-induced peripheral neuropathy in rats, which is evident by improved body weight, decreased thermal hyperalgesia, improved motor coordination, increased grip strength, improved nerve conduction velocity, and higher antioxidant enzymatic activities compared with cisplatin-treated rats[23].Body weight is frequently the most sensitive indicator of adverse effects of toxicants. The study revealed a decrease in the body weight following cisplatin administration, which may be attributed to the direct effect of cisplatin on growth, excessive breakdown of the tissue proteins or decreased both plasma and tissue proteins. Evidence has accumulated that lack of protection against reactive oxygen species (ROS) and lack of repair of DNA oxidative damage play a significant role in the progression of neurodegenerative diseases. Extensive research has linked neurodegenerative diseases with a hyperactive glutamatergic system, which results in the overactivation of NMDA receptors, excessive Ca2+ influx and eventual cell death.

Memantine is a neuroprotective agent able to inhibit the pathological features of NMDA receptor activation, and at the same time, it allows the necessary physiological and cognitive functions to remain intact. This drug has been shown to normalize the impairments in synaptic plasticity and cognition that typically follow excitotoxic neuronal injury. Neuroprotective drugs as memantine with clinical application in neurological diseases could decrease genomic instability in brain tissue in addition to improvement in cognitive functions.Recent studies have demonstrated that memantine diminishes neuronal cell damage evoked by staurosporine and doxorubicin. Corroborating those studies, memantine at 3 - 15 mg ⁄ kg decreased DNA damage in brain tissue, In this dose range, no stereo-typed behavior or signals of toxicity were observed, suggesting that the decrease in the brain DNA damage might be associated with neuroprotective effects of memantine. Micronucleus frequency increased, though without statistical significance, suggesting that memantine was unable to induce mutagenicity.

In a study using lipopolysaccharide infusion to induce neuroinflammatory damage, it showed that memantine decreases the probability of microglial activation, preventing the release of arachidonic acid and pro-inflammatory factors from neurons. Memantine increased the levels of brain-derived neurotrophic factor mRNA, which may mediate its neuroprotective effects, reversed loss of cell viability and decreased caspase-3 ⁄ 7 activities and ROS level induced by catechol (a component from cigarette smoke).

In the CNS, both in vivo and in vitro, previous studies indicated that the increase in pro inflammatory cytokines can be reduced by NMDAR antagonist.Memantine, a well characterized NMDAR antagonist, is used to treat dementia and Parkinson’s disease in clinic, and it also protected neurons from some models of neurological injury such as traumatic brain injury, ischemic stroke, spinal cord ischemia or neuroinflammation. Therefore, in the process of neuroinflammation, the release of Glutamate and the activation of NMDAR can enhance neuroinflammation and further deteriorate the CNS injury.

Excessive activation of CNS NMDA receptors induces Ca2+ overload and oxidative stress, leading to neurodegeneration. These observations spurred development of several NMDA antagonists, many of which are effective in animal models of neurodegeneration. Memantine can cause nearly complete inhibition of NMDA receptors. Memantine blocks the NMDA receptor pore, Therefore, synaptic transmission through NMDA receptors is maintained in the presence of memantine. On the other hand, this study suggests possible utility of a pharmacological strategy based on a drug that is already in widespread clinical use. The availability of usable drugs to block NMDA receptors, such as memantine, contrasts with the future promise of gene therapies or other as-yet unproven strategies that may be required for some other potential therapeutic targets[12, 34, 35].Withdrawal from chronic (6 month) alcohol ingestion produced learning deficits in rats in the Morris water maze. Treatment with memantine starting at the beginning of the withdrawal phase (20 mg/kg bolus followed by 1 mg/kg every 12 h for 4 weeks) resulted in a complete reversal of these behavioral impairments. Memantine (30 mg/kg/day; p.o.) for 2-3 weeks significantly improved the acquisition of the water maze task in mice without affecting swimming speed.

Memantine enhanced neurogenesis at therapeutically relevant concentrations in cortical cultures in vitro(the best effects were seen at 1 µM, with 140% of control neurogenesis) and in the DG and forebrain sub-ventricular zone in vivo (7.5 mg/kg p.o. once daily for 14 days, around 126% of control neurogenesis), in another study, acute treatment of rats with memantine (20 mg/kg) also led to an increase in neurogenesis in the hippocampus.Chronic dietary intake of memantine (31 mg/kg/day) for 14 days prevented death, convulsions and hippocampal damage induced by quinolinic acid[12, 38].Rats infused with quinolinic acid alone showed clear learning deficits in the T-maze whilst those infused in parallel with memantine (20 mg/kg/day) were able to acquire the task normally.

Memantine (5 mg/kg) showed no neuroprotection to mitigate cerebral injury after hypothermic circulatory arrest in a porcine model.while at dose (10 and 20 mg/kg) showed neuroprotection after traumatic brain injury (TBI) induced in adult rats with a controlled cortical impact device. TBI led to significant neuronal death in the hippocampal CA2 and CA3 regions (by 50 and 59%, respectively), by 7 days after the injury. Treatment of rats with memantine immediately after the injury significantly prevented the neuronal loss in both CA2 and CA3 regions[39, 40]. Memantine (10 mg/kg, i.p. 15 min after trauma) also significantly reduced lipid peroxidation levels in a rat model of closed head trauma in rats.

New data indicate the potential of memantine for the prevention of cognitive impairment produced by cancer therapy treatment. The effect of vincristine - (known to damage neurons), cytarabine –(known to produce damage in the cerebellum) and L-asparaginase– (known to be toxic through production of ammonia) were studied in rats in tests for exploration/cognition such as the hole board and water radial maze. In all models, clear impairment was noted which was prevented by chronic (14 days) treatment with memantine (10 mg/kg/day) when the test was done 24h after the last memantine dose. In a well-described rodent model, cisplatin exposure at 5–10 mg/kg/d produced several neurological deficits, including hind-limb foot splay, decreased fore- andhind-limb grip strength, ataxia, and skeletal muscle weakness, Moreover, cisplatin exposure resulted in the central–peripheral neuropathy in humans and in laboratory animals, including rats and monkeys[15, 16]hind limb paralysis was founded in 58% of the rats treated with cisplatin for 10 days, which attributed to neurotoxicity and concluded that the abnormal body posture, muscle weakness, and legs play accompanying cisplatin-intoxication in ratsю

In conclusion, memantine did not induce mutagenicity or DNA damage in blood or brain tissues, and it was able to protect against hydrogen peroxide-induced oxidative damage. These results corroborate the findings obtained in other studies, which have shown neuroprotective activities of memantine, besides its actions on memory and cognitive functions.