Neurodegenerative disorders pose a significant challenge to global healthcare systems
due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity,
characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In
this review article, we explore the involvement of calcium dysregulation in neurodegeneration and
neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds,
structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating
calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like
structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage-gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against
excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic
cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various
closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction
of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds
have been extensively studied, apart from amantadine and memantine, none have undergone clinical
trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the
efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.