Neuroprotective effects of various doses of topiramate against methylphenidate-induced oxidative stress and inflammation in isolated rat amygdala: the possible role of CREB/BDNF signaling pathway

Abstract

Methylphenidate (MPH) abuse damages brain cells. The neuroprotective effects of topiramate (TPM) have been reported previously, but its exact mechanism of action still remains unclear. This study investigated the in vivo role of various doses of TPM in the protection of rat amygdala cells against methylphenidate-induced oxidative stress and inflammation. Seventy adult male rats were divided into seven groups. Groups 1 and 2 received normal saline (0.7 ml/rat) and MPH (10 mg/kg), respectively, for 21 days. Groups 3, 4, 5, 6, and 7 were concurrently treated with MPH (10 mg/kg) and TPM (10, 30, 50, 70, and 100 mg/kg), respectively, for 21 days. elevated plus maze (EPM) was used to assess motor activity disturbances. In addition, oxidative, antioxidantand inflammatory factors and CREB, Ak1, CAMK4, MAPK3, PKA, BDNF, and c FOS gene levels were measured by RT-PCR, and also, CREB and BDNF protein levels were measured by WB in isolated amygdalae. MPH significantly disturbed motor activity and TPM (70 and 100 mg/kg) neutralized its effects. MPH significantly increased lipid peroxidation, mitochondrial GSSG levels and IL-1β and TNF-α level and CAMK4 gene expression in isolated amygdala cells. In contrast, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and CREB, BDNF Ak1, MAPK3, PKA, BDNF, and c FOS expression significantly decreased. The various doses of TPM attenuated these effects of MPH. It seems that TPM can be used as a neuroprotective agent and is a good candidate against MPH-induced neurodegeneration.

CREB Protects against Temporal Lobe Epilepsy Associated with Cognitive Impairment by Controlling Oxidative Neuronal Damage

“…To counteract the effects of ROS, there are antioxidant-producing systems including superoxide dismutase (SOD) which is an important antioxidant scavenging free radicals and preventing oxygen toxicity [18]. Interestingly, activation of CREB protects various cell types, including neurons, against ROS-induced damage [19][20][21].…”

Effects of topiramate on the ultrastructure of synaptic endings in the hippocampal CA1 and CA3 sectors in the rat experimental model of febrile seizures: the first electron microscopy report

“…Worthy of note is that the hippocampal neurons are particularly sensitive to a variety of excitatory amino-acid mediated cerebral damage. Recent observations of Motaghinejad et al [11][12][13] concerning neuroprotection of topiramate against methylphenidate-induced neurodegeneration in dentate gyrus and CA1 regions of the rat isolated hippocampus [11,13] and also in isolated rat amygdala [12] suggest that this antiepileptic drug can be used as a neuroprotective agent against apoptosis, oxidative stress and neuroinflammation. This could be partly caused by the activation of GABAA receptor, inhibition of AMPA/kainite receptor and probably via CREB/BDNF pathway [11][12][13].…”

“…Neurochemical studies suggest that the anticonvulsant and neuroprotective properties of this AED in various experimental models involve its multidirectional effect on the CNS, especially on the hippocampus structure, and are mainly based on the modulation of its GABA-ergic system. This is probably due to the involvement of AMPA/kainate and GABAA receptors, with antagonistic effects of TPM on glutamate receptors of the AMPA/kainate subtype, which play an essential role in excitotoxic neuronal damage [3,5,[11][12][13]17,32]. Worthy of note is that the hippocampal neurons are particularly sensitive to a variety of excitatory amino-acid mediated cerebral damage.…”

Possible neurological and mental outcomes of COVID-19 infection: A hypothetical role of ace-2\mas\bdnf signaling pathway

“…[ 6 ] On the other way, it was suggested that ACE-2 is one of the main enzymes, which by the mediation of some important protein such as Mas protein, regulates normal brain function and release of neurotrophic factors such as brain-derived neurotrophic factor (BDNF)[ 7 8 ] BDNF has a critical role in neurodevelopment, neurogenesis, inhibition of occurrences of neurodegeneration, and normal mood behavior such as mood stability and cognitive function. [ 9 ] According to this concept, it was approved that decrease activity of ACE-2 or reduction of its expression by some natural and acquired accident can disturb normal neurological and mental activity and can remain long term sequels. [ 8 10 11 ] Taken together according to recent studies, it was suggested that ACE-2 can be a target for COVID-19 in a strategic organ such as the brain and based on these data, it can be assumed that infection by COVID-19 may cause inhibition of ACE-2 and its downstream, BDNF, thus, it can instigate neurodegeneration (increase of oxidative stress, neuroinflammation, and apoptosis) and can probably cause mentally related disorders such as anxiety, depression, and cognition impairment.…”