Conclusions: Presentation with variable clinical and laboratory findings because of the multisystemic involvement may cause missed or delayed diagnosis in patients with LPI. The diagnosis of lysinuric protein intolerance should be considered in patients presenting with hyperferritinemia, elevated lactate dehydrogenase and hemophagocytic lymphohistiocytosis in addition to protein intolerance or aversion. In the present study we investigated whether physical exercise would prevent proline-induced memory deficits in Morris water maze tasks, as well as its effects on brain-derived neurotrophic factor (BDNF) immunocontent and brain acetylcholinesterase (AChE) activity in cerebral cortex and hippocampus of Wistar rats. Animals were divided into 4 groups: (1) control; (2) proline; (3) exercise and (4) proline plus exercise. Rats were submitted to proline administration from the 6th to 29th day of life, when the treatment was discontinued and the treadmill exercise was performed from day 30th to 60th day. Twenty-four hours after the last exercise session, the rats were subjected to behavioral testing in the water maze and then sacrificed for determination of BDNF and AChE activity. Proline impairs memory on spatial reference and working memory tasks and exercise prevented such effects. BDNF was reduced in both cerebral structures and AChE activity was increased only in hippocampus. Our results suggest that memory deficit caused by hyperprolinemia may be associated, at least in part, to decrease in BDNF immunocontent and increased AChE activity. Taken together, these findings reinforce the potential neuroprotective of physical exercise as an experimental therapeutic strategy to minimize cognitive deficits. Support by CNPQ, FAPERGS.