Adenosine kinase and adenosine receptors A₁R and A_2AR in temporal lobe epilepsy and hippocampal sclerosis and association with risk factors for SUDEP

Abstract

Objective:The "adenosine hypothesis of SUDEP" (sudden unexpected death in epilepsy) predicts that a seizure-induced adenosine surge combined with impaired metabolic clearance can foster lethal apnea or cardiac arrest. Changes in adenosine receptor density and adenosine kinase (ADK) occur in surgical epilepsy patients. Our aim was to correlate the distribution of ADK and adenosine A 2A and A 1 receptors (A 2A R and A 1 R) in surgical tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE/HS) with SUDEP risk factors. Methods: In 75 cases, patients were stratified into high-risk (n = 16), medium-risk (n = 11) and low-risk (n = 48) categories according to the frequency of generalized seizures before surgery. Using whole-slide scanning Definiens image analysis we quantified the labeling index (LI) for ADK, A 2A R, and A 1 R in seven regions of interest: temporal cortex, temporal lobe white matter, CA1, CA4, dentate gyrus, subiculum, and amygdala and relative to glial and neuronal densities with glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen (NeuN). Results: A 1 R showed predominant neuronal, A 2A R astroglial, and ADK nuclear labeling in all regions but with significant variation. Compared with the low-risk group, the high-risk group had significantly lower A 2A R LI in the temporal cortex. In HS cases with severe neuronal cell loss and gliosis predominantly in the CA1 and CA4 regions, significantly higher A 1 R was present in the amygdala in high-risk than in low-risk cases. There was no significant difference in neuronal loss or gliosis between the risk groups or differences for ADK labeling. Significance: Reduced cortical A 2A R suggests glial dysfunction and impaired adenosine modulation in response to seizures in patients at higher risk for SUDEP.Increased neuronal A 1 R in the high-risk group could contribute to periictal amygdala dysfunction in SUDEP. |

Regional microglial populations in central autonomic brain regions in SUDEP

“…This study was underpowered to detect regional differences in SUDEP cases with recent seizures compared to epilepsy controls; however, further studies of regional microglia responses and activation states in response to seizures are clearly warranted in SUDEP. In previous studies in SUDEP, we have recognized regional alteration in neuromodulators, including neuropeptidergic, adenosine, catecholaminergic, and serotonergic systems, [1][2][3]30,32 which may reflect network changes; as these neuromodulators also regulate microglial cells and their activation, 33 it is not inconceivable that these processes are inter-related. Activated microglial cells are also known to be increased in focal epilepsy pathologies, as focal cortical dysplasia, and correlate with duration of epilepsy, 34 with evidence of regional localization of the inflammation on C 11 PK11195 PET.…”

Relation between coffee consumption and risk of seizure‐related respiratory dysfunction in patients with drug‐resistant focal epilepsy

“…A recent preclinical study showed that acute administration of caffeine exacerbated tissue postictal hypoxia in the brain, because of a vasoconstrictive effect through A2 receptor antagonization. 32 Nocturnal FSs were more frequent in patients with moderate or high consumption than in those with no coffee consumption. However, duration of PIH did not differ between FSs occurring during sleep or while awake.…”

“…The mechanism underlying this paradoxical observation remains to be elucidated. A recent preclinical study showed that acute administration of caffeine exacerbated tissue postictal hypoxia in the brain, because of a vasoconstrictive effect through A2 receptor antagonization 32 . Nocturnal FSs were more frequent in patients with moderate or high consumption than in those with no coffee consumption.…”

The Good, the Bad, and the Deadly: Adenosinergic Mechanisms Underlying Sudden Unexpected Death in Epilepsy

“…Most of the experimentation pertinent to the role of adenosine in seizure-induced death has been conducted in acute seizure models, often in seizure-naïve animals. Epileptogenesis and the occurrence of repeated seizures alters the brain in ways that might be meaningful to SUDEP; for instance, an altered expression/function of ADK and adenosine receptors has been noted during epileptogenesis ( Patodia et al, 2020 ). Therefore, it would be beneficial to use models of epilepsy which feature spontaneous seizures and spontaneous seizure-induced death for investigating SUDEP.…”