Addex Therapeutics has made a significant stride in the field of drug discovery and development. Their recent findings, featured in the journal Brain, shed light on the potential therapeutic benefits of negative allosteric modulators (NAMs) targeting the mGlu5 receptor in enhancing post-stroke functional recovery. This breakthrough has ignited enthusiasm for the further exploration of a novel candidate drug called dipraglurant, a highly selective mGlu5 NAM, poised for Phase 2 clinical trials and currently undergoing evaluation in preclinical models of post-stroke recovery.
The process of functional recovery after a stroke hinges on the creation of new neural connections or the reactivation of existing ones. Accumulating evidence suggests that the mGlu5 receptor plays a pivotal role in modulating brain plasticity and function. To unravel the impact of mGlu5 inhibition on network reorganization and functional restoration following a stroke, researchers conducted experiments in preclinical stroke models. Their findings, presented in the publication titled “Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity,” demonstrated that administering mGlu5 NAMs daily for a span of 12 days, commencing either 2 or 10 days post-stroke, led to the restoration of somatosensory functions that had been impaired, without affecting the size of the infarcted area.
“The role of the mGlu5 receptor in multiple neurological indications and brain plasticity has been well documented, however this is the first time that inhibition of this receptor subtype has been linked to post-stroke functional recovery. We are very encouraged that the researchers specifically evaluated mGlu5 NAMs, highlighting the significant role this modality could play in the neural network recovery that is vital for patients to regain function.”
– Mikhail Kalinichev, PhD, Head of Translational Science at Addex
Remarkably, the signs of somatosensory recovery, as measured by the improved use of affected limbs, became evident within hours of treatment initiation and continued to progress over the subsequent 12 days. Importantly, this functional recovery was impeded when mGlu5 was activated by a positive allosteric modulator and was expedited in mice lacking the mGlu5 receptor. Moreover, utilizing optical intrinsic signal imaging, the researchers observed that mGlu5 inhibition effectively reversed disruptions in resting-state functional connectivity across the brain after a stroke. This effect was particularly pronounced in sensorimotor cortices on the opposite side of the lesion and bilaterally in visual cortices.
Crucially, the levels of mGluR5 protein in both mice and tissue samples from stroke patients remained unchanged after a stroke event. This led to the conclusion that a mGluR5-dependent mechanism of maladaptive plasticity depresses the neural circuitry responsible for sensorimotor function after a stroke, and this can be rectified through mGluR5 inhibition. These findings suggest a promising avenue for post-acute stroke therapy, where treatment with mGluR5 NAMs, coupled with rehabilitative training, may offer a groundbreaking approach to enhance post-stroke recovery.
In essence, Addex Therapeutics‘ cutting-edge research has unveiled a potential game-changer in the realm of post-stroke treatment. Their work with mGlu5 NAMs and the promising results they have achieved in restoring brain function and connectivity following a stroke holds great promise for individuals seeking improved outcomes in their post-acute stroke recovery journey. This innovative approach, combined with rehabilitative efforts, opens up new possibilities for enhancing the quality of life for stroke survivors.