Dr. Santoro joined Shamloo’s lab in March 2021 focusing his research on Parkinson’s disease, neuronal vulnerability, and identification of therapeutic markers in relation to α-synucleinopathies. Prior to his arrival at Stanford, he held a position as a clinical monitor at Syneos Health where he gained key knowledge needed to translate lab-based findings into clinical and commercial applications. Previously, Dr. Santoro held a postdoctoral position at the University of Aberdeen (Scotland, UK) working on amyloid-beta extracts from Alzheimer’s disease patients. During his postdoctoral research, Dr. Santoro designed and optimized a cost-effective and rapid assay for the measurement of toxic amyloid-beta species in human biofluids. In 2017, he obtained his Ph.D. (4-year program) at the University of Aberdeen on Parkinson’s disease (PD), immunology, and behavior. The major findings Ph.D. findings were the following: 1) the characterization of a small protein called HMGB1 as an inflammatory mediator in PD; 2) the motor and non-motor behavioral characterization of three neurotoxin based mouse models of PD, 3) the characterization of the innate immune response in PD through the toll-like receptor signaling pathways 4) evaluation of the effects of chronic systemic inflammation on both resident and infiltrating immune cells in the CNS. In 2012 Dr. Santoro attained his Pharm.D. in chemistry and pharmaceutical technology (5-year program) at the University of Calabria (Italy) during which he undertook an internship at the King’s College London (SGDP Centre) and worked for over a year on a rat model of stroke.

Boards, Advisory Committees, Professional Organizations

  • Member, Society for Neuroscience (2021 - Present)

Professional Education

  • Bachelor of Science, Unlisted School (2012)
  • Doctor of Philosophy, University Of Aberdeen (2018)
  • Ph.D., University of Aberdeen, Scotland, UK, Parkinson's disease (2018)
  • Pharm.D., University of Calabria, Italy, Pharmacy, chemistry, and pharmaceutical technology (2012)
  • Pharmacist License, University of Calabria, Italy, Pharmacy (2012)

Stanford Advisors


  • Michael J. Green, Alam Jahangir, Denise Briggs, Alex Ferris, Mehrdad Shamloo, Matteo Santoro. "United States Patent 63/587,897 Provisional Patent: KINASE INHIBITORS AND METHODS OF USE THEREOF", Oct 4, 2023


  • Globo-temporal profile of neurodegeneration in the 6-hydroxydopamine mouse model of Parkinson's disease, Stanford University (March 7, 2021 - Present)

    Extensive efforts to unravel the intricate mechanisms underlying Parkinson's disease (PD) have failed to lead to disease-modifying treatment breakthroughs. The limited progress in PD pharmacotherapy can be ascribed, in part, to the absence of research models that reproduce all the distinct pathological hallmarks of PD within a single animal species. Moreover, insufficient attention has been directed towards extra-nigrostriatal regions prodromally affected in PD patients. These more extended changes underlie the occurrence of non-motor symptoms. Among the models that induce a PD-like phenotype, the infusion of 6-hydroxydopamine (6-OHDA) into the mouse brain has gained prominence since 2012, with most investigations into pathology focusing on the nigrostriatal region. In this study, we delve deeply into methodological considerations pertaining to this model, such as sex differences, progression rate, extent of nigrostriatal lesions, compensatory mechanisms, and the neuroinflammatory response that precedes neuronal degeneration in C57BL/6 mice subjected to varying dosages of 6-OHDA (5, 10, or 20 µg) infused into the dorsal striatum. We show for the first time the loss of TH+ neurons spanning the entire brain, along with compensatory changes, using immunolabeling, iDISCO+, light sheet fluorescence microscopy, and image quantification based on fMRI and machine learning tools. Furthermore, as an integral part of our pursuit to identify and validate potential therapeutic targets, we comprehensively assessed changes in neuroinflammatory pathways and abnormal cellular signaling preceding neuronal degeneration within the nigrostriatal region. Overall, this detailed characterization of neuronal degeneration enhances our understanding of the pathology, temporal profile of neuronal degeneration, and sex differences in the 6-OHDA mouse model and may guide neurotherapeutic development in PD.



  • Discovery of DAPK1 and CMGC kinase inhibitors for the treatment of brain disorders (March 7, 2021 - Present)

    The Ca2+/calmodulin-regulated serine/threonine kinase death-associated protein kinase 1 (DAPK1) is a promising therapeutic target for neurological conditions, neurodegenerative disorders, and p53-mutation cancers. Herein, we present the development and synthesis of novel type-I DAPK1 inhibitors. Employing rational design and computational docking, we aimed to enhance the potency and stability of a previously documented DAPK1 inhibitor (1001) in liver microsomes. Drawing upon considerations of pharmacokinetics (PK) and metabolic stability, our efforts led to the identification of three noteworthy analogs from a pool of 77 candidates. Among these, 1044 emerged as the most selective and 1055 as the most potent, while 1074 displayed the optimal in vitro and in vivo PK profile.
    Beyond kinase selectivity, 1044 displayed potent attenuation of human microglia phagocytic activity and enhancement of neurite outgrowth. Our evidence suggests the key involvement of DAPK1 in microglial activation and lysosomal regulation of the autophagosomes. Compound 1044 is also a potent inhibitor of while dual-specificity tyrosine phosphorylation-regulated kinase DYRK1A and DYRK2, which modulate synaptogenesis and axonal regeneration. A-posteriori computational docking analysis showed a weak correlation with the in-vitro IC50 readouts from 50 compounds. Our future work will focus on the identification of potent inhibitors capable of crossing the blood brain barrier (BBB) in order to address central nervous system (CNS) neurodegenerative and neurodevelopmental disorders.



All Publications

  • Neurochemical, histological and behavioral profiling of the acute, sub-acute and chronic MPTP mouse model of Parkinson's disease. Journal of neurochemistry Santoro, M., Fadda, P., Klephan, K. J., Hull, C., Teismann, P., Platt, B., Riedel, G. 2022


    Parkinson's disease (PD) is a heterogeneous multi-systemic disorder unique to humans characterized by motor and non-motor symptoms. Preclinical experimental models of PD present limitations and inconsistent neurochemical, histological, and behavioral readouts. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD is the most common in-vivo screening platform for novel drug therapies; nonetheless, behavioral endpoints yielded amongst laboratories are often discordant and inconclusive. In this study, we characterized neurochemically, histologically, and behaviorally three different MPTP mouse models of PD to identify translational traits reminiscent of PD symptomatology. MPTP was intraperitoneally (i.p.) administered in three different regimens: i) acute - four injections of 20 mg/kg of MPTP every 2 hours; ii) sub-acute - one daily injection of 30 mg/kg of MPTP for 5 consecutive days; and iii) chronic - one daily injection of 4 mg/kg of MPTP for 28 consecutive days. A series of behavioral tests were conducted to assess motor and non-motor behavioral changes including anxiety, endurance, gait, motor deficits, cognitive impairment, circadian rhythm and food consumption. Impairments in balance and gait were confirmed in the chronic and acute models respectively, with the latter showing significant correlation with lesion size. The sub-acute model, by contrast, presented with generalized hyperactivity. Both, motor and non-motor changes were identified in the acute and sub-acute regime where habituation to a novel environment was significantly reduced. Moreover, we report increased water and food intake across all three models. Overall, the acute model displayed the most sever lesion size while across the three models striatal dopamine content (DA) did not correlate with behavioral performance. The present study demonstrates that detection of behavioral changes following MPTP exposure is challenging and does not correlate with the dopaminergic lesion extent.

    View details for DOI 10.1111/jnc.15699

    View details for PubMedID 36184945

  • Role of Histone Deacetylases (HDACs) in Epilepsy and Epileptogenesis. Current pharmaceutical design Citraro, R., Leo, A., Santoro, M., D'agostino, G., Constanti, A., Russo, E. 2017; 23 (37): 5546-5562


    Emerging evidence suggests that epigenetic mechanisms are involved in different brain functions such as the development of the nervous system and normal neuronal function. At the same time, it has been proposed that several neurological diseases are in part, caused by aberrant epigenetic modifications. Nevertheless, the mechanisms underlying pathological alterations in the brain genome are not completely understood.Post-transcriptional histone acetylation is a major mechanism of chromatin remodeling, contributing to epigenetic regulation of gene transcription. Histone deacetylases (HDACs) are a family of proteins involved in both physiological and pathological conditions by regulating the status of chromatin histone acetylation. It is now becoming clear that epigenetic regulatory mechanisms may also play a major role in epilepsy; modulation of chromatin structure through histone modifications has emerged as an important regulator of gene transcription in the brain and altered histone acetylation seems to contribute to changes in gene expression associated with epilepsy and the epileptogenic process. Histone modification is crucial for regulating neurobiological processes such as neural network function, synaptic plasticity, and synaptogenesis which also contribute to the pathophysiology of epilepsy.The role of epigenetics in epilepsy development is a new and emerging research area; the present article reviews the recent findings on the role played by HDACs and the possible function of different histone modifications in epilepsy and epileptogenesis. Inhibitors of HDACs (HDACIs) have been tested in different experimental models of epilepsy with some success. We also review the results from these studies, which indicate HDACIs as potential new therapeutic agents for the treatment of human epilepsy.

    View details for DOI 10.2174/1381612823666171024130001

    View details for PubMedID 29076408

  • In-vivo evidence that high mobility group box 1 exerts deleterious effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model and Parkinson's disease which can be attenuated by glycyrrhizin. Neurobiology of disease Santoro, M., Maetzler, W., Stathakos, P., Martin, H. L., Hobert, M. A., Rattay, T. W., Gasser, T., Forrester, J. V., Berg, D., Tracey, K. J., Riedel, G., Teismann, P. 2016; 91: 59-68


    High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is released during tissue damage from immune and non-immune cells - including microglia and neurons. HMGB1 can contribute to progression of numerous chronic inflammatory and autoimmune diseases which is mediated in part by interaction with the receptor for advanced glycation endproducts (RAGE). There is increasing evidence from in vitro studies that HMGB1 may link the two main pathophysiological components of Parkinson's disease (PD), i.e. progressive dopaminergic degeneration and chronic neuroinflammation which underlie the mechanistic basis of PD progression. Analysis of tissue and biofluid samples from PD patients, showed increased HMGB1 levels in human postmortem substantia nigra specimens as well as in the cerebrospinal fluid and serum of PD patients. In a mouse model of PD induced by sub-acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), systemic administration of neutralizing antibodies to HMGB1 partly inhibited the dopaminergic cell death, and reduced the increase of RAGE and tumour necrosis factor-alpha. The small natural molecule glycyrrhizin, a component from liquorice root which can directly bind to HMGB1, both suppressed MPTP-induced HMGB1 and RAGE upregulation while reducing MPTP-induced dopaminergic cell death in a dose dependent manner. These results provide first in vivo evidence that HMGB1 serves as a powerful bridge between progressive dopaminergic neurodegeneration and chronic neuroinflammation in a model of PD, suggesting that HMGB1 is a suitable target for neuroprotective trials in PD.

    View details for DOI 10.1016/j.nbd.2016.02.018

    View details for PubMedID 26921471

    View details for PubMedCentralID PMC4867789

  • Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease. Glia Martin, H. L., Santoro, M., Mustafa, S., Riedel, G., Forrester, J. V., Teismann, P. 2016; 64 (3): 386-95


    Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post-mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In wild-type mice MHC II levels in the ventral midbrain were upregulated 1-2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP-induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon-γ or tumour necrosis factor-α in the brain after MPTP treatment, as was found in wild-type mice. However, interleukin-1β was significantly increased in both wild-type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II-mediated T cell activation is required for the full expression of pathology in this model of PD.

    View details for DOI 10.1002/glia.22935

    View details for PubMedID 26511587

    View details for PubMedCentralID PMC4855685