Melatonin improves memory defects in a mouse model of multiple sclerosis by up-regulating cAMP-response element-binding protein and synapse-associated proteins in the prefrontal cortex

Abstract

Multiple sclerosis is a progressive autoimmune disorder of the myelin sheath and is the most common inflammatory disease of young adults. Up to 65% of multiple sclerosis patients have cognitive impairments such as memory loss and difficulty in understanding and maintaining attention and concentration. Many pharmacological interventions have been used to reverse motor impairments in multiple sclerosis patients; however, none of these drugs improve cognitive function. Melatonin can diffuse through the blood-brain barrier and has well-known antioxidant and anti-inflammatory properties with almost no side effects; it is, therefore, a promising neuroprotective supplement for many neurological diseases, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, ischemic stroke, and fibromyalgia. However, only some researches have assessed the effect of melatonin on cognitive dysfunction in multiple sclerosis. Here, we evaluated the effects of melatonin supplementation on memory defects induced by cuprizone in a mouse model of multiple sclerosis. Cuprizone (400 mg/kg) and melatonin (80 mg/kg) were administered to SWR/J mice daily for 5 weeks. Open field, tail-flick, and novel object recognition behavioral tests were performed. Also, expression of cAMP-response element-binding protein, synaptophysin, and postsynaptic density protein 95 were measured in the prefrontal cortex. Melatonin significantly improved the memory defects induced by cuprizone toxicity by up-regulating cAMP-response element-binding protein and by increasing expression of the synapse-associated synaptophysin and postsynaptic density protein 95 genes in the prefrontal cortex. These results indicate that melatonin may provide protective effects against memory impairments associated with multiple sclerosis.

Protective effects of melatonin on changes occurring in the experimental autoimmune encephalomyelitis model of multiple sclerosis

“…In a recent work about MS, it was concluded that a combination therapy may be more effective, especially using agents that target neuroinflammation and neurodegeneration, as they may exert synergistic actions, and melatonin is amongst them (Martinez and Peplow, 2020). The effectiveness of melatonin has also been seen to significantly improve memory defects by up-regulating cAMP-response element-binding protein and by increasing the expression of the synapse-associated synaptophysin and postsynaptic density protein 95 genes in the prefrontal cortex (Alghamdi and AboTaleb, 2020).…”

Melatonin Improves Short-Term Spatial Memory in a Mouse Model of Alzheimer’s Disease

“…In our study, we thus used the highest prophylactic dose of MLT (80 mg/kg), which does not produce any signs of toxicity in mice. 14 , 18 , 66 This high dose of MLT is found to be a potent antioxidant and anti-inflammatory which improved memory outcomes and locomotor activity in multiple sclerosis animal model. 14 , 18 Moreover, this high dose of MLT altered the T effector/regulatory balance which therefore protect against experimental autoimmune encephalomyelitis animal model.…”

“…We used the highest prophylactic dose of MLT (80 mg/kg), which does not produce any signs of toxicity in mice. 14 , 18 , 47 …”

“… 16 Chronic MLT administration can enhance synaptogenesis and synaptic function, and can also preserve glial cell structure in the AD rat brain. 17 , 18 In addition, MLT efficiently prevents the formation and accumulation of Aβ and neurofibrillary tangles in the brains of AD model animals. 19 , 20 MLT also improves performance in novel object recognition and passive avoidance tasks in an adult ICR AD mouse model, 21 and spatial memory assessed by Morris water maze and Y-maze tasks in young and aged AD model mice.…”

The Effect of Melatonin and Exercise on Social Isolation-Related Behavioral Changes in Aged Rats

“…Melatonin (MLT) is a neurohormone secreted from the pineal gland and extra-pineal sources that exhibits a wide variety of regulatory functions ( Alghamdi, 2018 ). One previous study reported that MLT enhanced memory by upregulating synapse-associated synaptophysin and postsynaptic density protein 95 genes in the prefrontal cortex ( Alghamdi and AboTaleb, 2020 ). Other studies found that MLT can improve memory impairment though brain-derived neurotrophic factor/cAMP-response element binding protein expression in AD mice ( Labban et al, 2021 ).…”