cAMP/PKA-CREB-BDNF signaling pathway in hippocampus of rats subjected to chemically-induced phenylketonuria

Abstract

Phenylketonuria (PKU) is an inborn error disease in phenylalanine metabolism resulting from defects in the stages of converting phenylalanine to tyrosine. Although the pathophysiology of PKU is not elucidated yet, the toxic effect of phenylalanine on the brain causes severe mental retardation. In relation to learning and memory, the hippocampal PKA / CREB / BDNF pathway may play a role in learning deficits in PKU patients. This study aimed to investigate PKA/CREB/BDNF pathway in hippocampus of chemically induced PKU rats with regard to gender. Sprague-Dawley rat pups were randomized into two groups of both genders. To chemically induce PKU, animals received subcutaneous administration of phenylalanine (5.2 mmol / g) plus p-chlorophenylalanine, phenylalanine hydroxylase inhibitor (0.9 mmol / g); control animals received 0.9% NaCl. Injections started on the 6th day and continued until the 21st day after which locomotor activity, learning and memory were tested. In male PKU rats, locomotor activity was reduced. There were no differences in learning and memory performances of male and female PKU rats. In PKU rats, pCREB / CREB levels in males was unchanged while it decreased in females. Elevated PKA activity, BDNF levels and decreased pCREB/CREB ratio found in female PKU rats were not replicated in PKU males in which BDNF is decreased. Our results display that in this disease model a gender specific differential activation of cAMP/PKA-CREB-BDNF signaling pathway in hippocampus occurs investigation of which can help us to a better understanding of disease pathophysiology.

Rat PKU Model Display Gender-Based Neuroinflammatory Changes: Proinflamatuary Cytokines and Lipid Peroxidation

“…To assess the involvement of neuroinflammation and oxidative stress in PKU, a chemically-induced PKU model in male and female rats was established as performed previously (22) Muğla Sıtkı Koçman Üniversitesi Tıp Dergisi 2024;11( 1 and the selected parameters were analyzed in PFC homogenates. Neurotransmitter systems were assessed through monoaminergic neurotransmitter activities, while the lipid peroxidation products, antioxidant enzyme activities, and cytokines were analyzed to evaluate oxidative stress response and neuro-inflammation.…”

“…PKU animals received phenylalanine (5.2 mmol/g of body weight) injection daily while the phenylalanine hydroxylase inhibitor and tyrosine hydroxylase inhibitor (20), p-Cl-Phe (0.9 mmol/g of body weight) injection was administered every other day. For all groups, injections started on the postnatal 6 th day and continued until the postnatal 20 th day (19,21,22). Animals were euthanized by decapitation without anesthesia and the brain was rapidly excised on a Petri dish placed on ice.…”

Disorder of neuroplasticity aggravates cognitive impairment via neuroinflammation associated with intestinal flora dysbiosis in chronic heart failure

“…Notably, cAMP signaling plays a vital role in brain physiological mechanisms, involving neuronal activity, energy production, metabolic processes, and synaptic function. A decline in cAMP levels deactivates PKA, reducing phosphorylated CREB (p-CREB) level [ 66 , 67 ]. The reduction in p-CREB levels, a nuclear transcription factor for learning, memory, and cognitive function, leads to decreased neurotrophic factors, particularly BDNF [ 68 ].…”

Curculigoside rescues hippocampal synaptic deficits elicited by PTSD through activating cAMP‐PKA signaling

“…The hippocampal PKA/CREB/BDNF pathway is closely related to learning and memory (Cicek et al, 2022). The function of CREB is dominantly regulated by phosphorylation at Ser133 (Zhao et al, 2021).…”