Ischemia refers to a lack of blood flow to a specific area of the brain, often resulting in damage to brain tissue. It can lead to a massive depolarization of neurons, known as anoxic depolarization, which can ultimately result in neuronal death. Adenosine is a neuromodulator that accumulates extracellularly in response to various conditions such as ischaemia, hypoxia, and seizures. It activates four metabotropic receptors, A1, A2A, A2B, and A3, and has been implicated in numerous physiological and pathological processes in the nervous system. Adenosine plays a key role in regulating the sleep-wake cycle and in modulating pain, inflammation, and synaptic plasticity. It has also been shown to have neuroprotective effects in certain contexts, such as reducing damage following ischaemia. However, excessive adenosine release can contribute to neuronal injury and death, particularly in the context of ischaemic or epileptic events. Striatal medium spiny neurons (MSN) are particularly vulnerable to ischaemia. Blocking A2A receptors can reduce the damage to striatal medium spiny neurons that occurs after an ischemic event. However, the specific cellular mechanisms that lead to this reduction in damage are still not fully understood. When neurons are exposed to various stressors, such as hypoxia or oxidative stress, they can release adenosine, which can activate A2A receptors and lead to further damage. By blocking A2A receptors, this cycle of damage can be disrupted, leading to neuronal protection.
In a new study published in the British Journal of Pharmacology, Dr. Elisabetta Coppi from University of Florence and Professor Alasdair Gibb from University College London conducted patch-clamp recordings in MSNs in acute striatal slices to examine the processes by which an ischaemic-like insult caused by in vitro OGD leads to functional disability in these cells and investigated the role of A2A receptors in these processes.
Dr. Coppi and Professor Gibb showed for the first time, that blocking A2A receptors selectively in rat striatal slices protects MSNs against OGD-mediated insults by delaying the onset of anoxic depolarization. According to the findings, early decrease of neuronal excitability and energy demand by K+ current augmentation may be an effective therapeutic goal for post-ischaemic brain injury. The authors explain their experimental setup and results for examining the MSN response to OGD. They utilized a pipette solution with a low chloride concentration, which results in outward currents during GABAA receptor activation, which they thought unlikely to contribute to the total anoxic depolarization current. The anoxic depolarization current is mostly carried by Na+ and Ca2+ ion entry, which causes a series of detrimental events that eventually lead to neuronal death. They discuss two glutamate-dependent elements of the anoxic depolarization signal, NMDA receptor- and AMPA receptor-dependent, with the suggestion that the NMDA receptor subtype was likely responsible for the majority of the current. Several aspects supported this, including reduced Mg2+ block after OGD-induced depolarization, greater glutamate affinity of NMDA receptors (compared to AMPA receptors), and the likely degree of receptor desensitization after extended agonist exposure.
The authors discuss that in striatal MSNs, energy failure and loss of ion gradients across the cell membrane will result in channel opening and potassium accumulation in the extracellular space, leading to anoxic depolarization and permanent damage. The study suggested that blocking A2A receptors can reduce the damage caused by ischaemia by preventing A2A receptor-dependent inhibition of potassium channels. The findings suggest that voltage-dependent Na+ channels are not implicated in the first changes in membrane permeability that lead to anoxic depolarization onset, but they do accelerate and aggravate the attainment of maximum anoxic depolarization amplitude. Coppi & Gibb show that OGD insults performed under control settings drastically reduced sEPSC (spontaneous excitatory postsynaptic current) frequency, indicating a reduction in neurotransmitter glutamate release during the early stages of OGD which is counteracted by selective A2A receptor activation, supporting the hypothesis of A2A receptors facilitating glutamate release during OGD. Hence blocking the A2A receptors will tend to be neuroprotective by favouring reduced glutamate release.
In summary, the authors showed that blocking A2A receptors during OGD protects striatal MSNs by lowering anoxic depolarization amplitude and delaying anoxic depolarization emergence, potentially by increasing K+ currents. These findings might aid in the development of A2A receptor antagonists as a novel pharmaceutical strategy for treating acute ischemic injury during brain ischaemia. More research is urgently needed to fully understand the mechanisms involved and to translate the use of A2A receptor blockers to the clinic.
Coppi E, Gibb AJ. Selective block of adenosine A2A receptors prevents ischaemic‐like effects induced by oxygen and glucose deprivation in rat medium spiny neurons. British Journal of Pharmacology. 2022;179(20):4844-56.