الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 105 |  |  |
| | | from | 105 | | |
Abstract
AD is considered as the most common age related neurodegenerative disorder. It is a progressive and unremitting disease which influence wide areas of the cerebral cortex and hippocampus. AD is characterized by cognitive dysfunctions, behavioral and social deterioration. It is characterized by extracellular accumulation of insoluble forms of β amyloid plaques, as well as in the walls of blood vessels, and intraneural aggregation of the microtubule protein tau in neurofibrillary tangles.
Many aspects of the AD were observed following ICV injection of STZ. This compound is commonly used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance. STZ treatment causes enhanced neuroinflammatory mediators and altered redox state that contribute to the neurodegenerative processes. The STZ treated animals develop insulin resistant brain state which is associated with memory impairment, progressive cholinergic deficits and glucose hypometabolism that share many features in common with SAD in humans.
It is well accepted that exercise is the corner stone of a healthy lifestyle and the frontline defense for primary and secondary prevention of many metabolic and cardiovascular diseases. Further, it is associated with increased cerebral blood flow and reduced brain tissue loss, increased synapse plasticity and, importantly, de novo neurogenesis in the dentate gyrus supporting the idea that physical activity leads to anatomical and physiological alterations in the brain.
The myokine irisin was identified, in 2012, as a muscle-derived factor that is suggested to be released from the muscle immediately after exercise. It regulates energy metabolism by inducing browning of white adipose tissue and thus dissipates chemical energy in the form of heat. Therefore, irisin has drawn the attention as a preventive and therapeutic target to treat obesity and metabolic diseases like type 2 DM. Given that exercise is known to improve neurogenesis and slow the progression of neurodegenerative diseases, irisin may stand beyond the neuroprotective effects of exercise,
Carnosine is an endogenously synthesized dipeptide (β-alanine and L-histidine) which is present, in particular, in the brain, cardiac muscle, kidney, stomach, olfactory bulb and in large quantities in skeletal muscle. For its anti-oxidant effect, it is suggested to prevent aging, AD and diabetic complications.
Taken together, the aim of the present work was to study the potential mechanisms of muscular exercise and L-Carnosine in improving the cognitive function in a rat model of Alzheimer’s disease and examining their influence on serum and hippocampal irisin and brain insulin resistance.
In the present work, 40 rats received left ICV injection of either saline (control, n=10) or STZ (n=30) to induce AD model. Three weeks later, memory dysfunction was verified using neurobehavioral tests. Then, affected rats were either assigned to a swimming paradigm for 5 weeks, received oral carnosine (100 mg/kg/day) for 5 weeks or underwent normal daily activity and received no treatment (10 rats each). At the end of experimental period, rats were once more subjected to behavioral assessment and then sacrificed for biochemical analysis (hippocampal β amyloid peptide, hyperphosphorylated tau protein, oxidative stress markers, relative expression of p-IR and p-PI3K proteins, hippocampal and serum irisin and CSF glucose levels) and histological examination of the hippocampus.
By comparing results of neurobehavioral, biochemical tests and histological examination, the present study showed that untreated STZ injected rats have lower results in all behavioral tests, increased levels of hippocampal phosphorylated tau proteins, β-amyloid peptide and CSF glucose level, marked oxidative stress, decreased relative expression of p-IR and p-PI3K proteins and decreased hippocampal irisin compared to control rats, which proved the development of AD. Physical exercise and carnosine intake reversed these derangements, possibly through their influence on hippocampal irisin level and their antioxidative effect. Increased hippocampal irisin level was associated with activation of PI3K signaling pathway and IR phosphorylation. So, irisin may help in decreasing brain insulin resistance and enabling the brain to utilize glucose more efficiently. These effects could be the reason for decreased amyloid peptides and phosphorylated tau proteins, amelioration of oxidative stress and enhancement of memory functions observed after chronic swimming and carnosine supplementation.
Based on the formerly mentioned findings, the present study suggests that physical exercise and carnosine supplementation can improve AD deficits through their stimulatory effect on hippocampal irisin level. Irisin was found to have neuroprotective effects through improving insulin resistance state, its anti-amyloid effect and a probable antioxidative role.